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The movie opens with Dr. Miranda Grey (Halle Berry) having a psychiatric session with one of her mental patients named Chloe (Penelope Cruz).
Chloe talks about an event that continuously happens to her, a man comes into her room at night, enters her body and she starts to burn from the inside out. She says this man is the devil. Dr. Miranda Grey is skeptical about Chloe's claims. She thinks Chloe is talking about her stepfather who raped Chloe. Chloe then starts talking about what she did to her stepfather: she cut his throat and watched him slowly bleed to death. Chloe says that killing him was the only way to 'help him stop'. Miranda asks Chloe "to help him stop what?" and Chloe bursts in a crazy angry voice "to help him stop fucking me." Chloe is now angry that Miranda is not listening to her. She says that Miranda is listening with her brain but not her heart. Miranda asks Chloe to trust her, and Chloe responds by saying "You can't trust somebody when they think you're crazy."
Miranda ends the session with Chloe. She goes to see one of her colleagues, Dr. Phil Parsons, another psychiatrist. She then goes to see the boss, Doug, who is also her husband. She expresses her concern about Chloe and says that she doesn't know what to do anymore. Chloe keeps "embellishing her rape story" and Miranda feels their sessions are going nowhere. Her husband, Doug, then asks Miranda to come and look at the mirror with him. He gives her a glass of water which he instructs for her to throw onto the mirror. Doug says that the distorted reflection is something like what Chloe sees. Miranda figures out that she is the mirror and Chloe is the image. Miranda then asks Doug what his role is in all of this. Doug says that since he can see both of them, he must be God. (Important) Doug laughs. The couple kiss. They are interrupted by another doctor who opens the door to Doug's office. It's Pete (Robert Downey Jr.) The three chat for a bit and Doug has to leave. Miranda still has to do some things in her office so she stays. Pete asks Miranda if she would like to get some pizza with him. She turns him down. He keeps persisting until she says she hates pizza.
Miranda goes into her office and does some work. Afterwards she goes for a swim. When she finishes her laps she gets ready for home. It is raining outside. Pete shows up behind her with an umbrella and walks her to her car. On the way home there is an accident on the road. The sheriff (Sheriff Ryan) tells her she can't pass through, and he gives her directions for a de-tour. Sheriff Ryan who is her husband's best friend tells her the de-tour is by this bridge, the same bridge that he and Doug used to go fishing at.
As she drives through the bridge Doug calls and Miranda tells him she will be a little late because of an accident. Then they lose connection and the cell phone goes dead. The rain is pouring now and Miranda can barely see the road. Suddenly she sees the figure of a girl ahead of her. She screams and turns the wheel and she ends up on a ditch beside the road. She exits her car and comes up to the girl. The girl is wearing a night gown and she has cuts all over her body. Miranda is shocked and tells the girl that she is a doctor and she can help her. The girl is shaking her head and doesn't want Miranda to touch her. Miranda takes off her jacket and tries to put it on the girl. When she touches the girl, the girl bursts into flames and Miranda feels the flames because she screams also. Then she blacks out.
When Miranda wakes up she is in one of the mental patient's cells with glass walls. One of the nurses come inside to give her a shot and Miranda becomes hysterical and starts throwing things and screaming that "There better be a good explanation why I'm in here". Pete (Robert Downey Jr.) then arrives and they start to have a discussion. Miranda doesn't understand. She asks for her husband. Pete asks her to try to remember the last few events she experienced. She starts telling Pete what she remembers and the last thing she remembers is going inside the house and seeing Doug sitting on the couch and smoking a cigar. Pete asks her if they ever had any serious problems in their marriage. She says no. Eventually Pete tells Miranda that Doug is dead and that she was the one who killed him. She starts acting hysterical again and the security guards and nurse come inside to restrain her and give her another shot.
The scene switches to the lounge area of the mental ward where the patients are hanging around playing games and doing other activities. Chloe (Penelope Cruz) sees her and comes up to her. She tells Miranda that she's one of them now and that no one can hear her. She's invisible now. No matter how much she tries to tell them the truth, no one will believe her. She asks Miranda if she is afraid. Miranda says No and Chloe says that she should be. Then Chloe tosses a newspaper clipping to Miranda. It is about the brutal killing that Miranda committed in their home.
Miranda is now back in her cell she looks at the glass. An invisible presence breathes on it and writes the words Not Alone on the glass. (Important) Miranda goes to sleep. She sees images and she tries to rationalize with herself saying she is only dreaming. A presence keeps circling her and she goes into a corner and buries her head in her arms as if trying to protect herself. Then someone touches her, she screams but when she looks up it is the nurse. The nurse gives her some pills to take and tells her it's take a shower. She is led to the shower room which consists of one big room with several showers on the ceiling and she has to share it with about 20 other female patients. Miranda feels uncomfortable yet she joins the other patients to take a shower. She is now surrounded by a bunch of women. Somehow, however, the girl who she saw at the bridge keeps appearing to her, at the corner of her eye. Every time she turns it's just one of the patients. The girl from the bridge keeps taunting her and is now pushing her around the shower room. The other patients are getting irritated that she is bumping into them. Then the girl from the bridge starts slashing Miranda and Miranda tries to protect her face by covering it with her arm. Her left arm gets badly slashed and she falls to the floor. By this time all the other patients have run out of the shower room.
Miranda is taken into the administrative room where the nurses, guards and her doctor Pete questions her about the slashing. They think she did this to herself. She tells them about the girl. They don't believe her.
In a private session with Pete she asks him if he had ever wanted to have an affair with her when they were colleagues. He says yes. She asks him why didn't they. He says it's because she was married to the boss.
Later on Miranda approaches Dr. Phil Parsons, who is now the boss since Doug died. She talks to him from behind the fence and says that she doesn't think Pete is the best doctor for her because of personal issues. Dr. Parsons says he is the best doctor available on staff especially for Miranda's case. Miranda looks to the building and notices Pete looking out the window watching her talk to Dr. Parsons.
Miranda's lawyer, Teddy now arrives at the mental institute. He discusses with Miranda the terms of her case. He says they will try to plead temporary insanity. Miranda doesn't like this idea because she still does not believe there is anything wrong with her. Sheriff Ryan then comes to sit down with them and asks Miranda some questions about the murder. Sheriff Ryan suddenly becomes emotional because Doug was his best friend. He starts screaming at Miranda asking why she killed him the way she did. Then he showed her some pictures of the crime scene and it showed blood splattered all over the living room and Doug's body in pieces.
Later on they are in Dr. Parson's office (Miranda, Pete, Dr. Parsons and some security guards). They discuss her upcoming trial. Miranda notices a picture behind Dr. Parsons. It is the girl from the bridge. Miranda asks who the girl is.
Dr. Parsons says it is his daughter Rachel. Miranda tells Pete and Dr. Parsons that it's the same girl that she saw at the bridge. Dr. Parsons says it cannot be so, because Rachel has been dead for 4 years.
Back in her cell Miranda talks to the ghost of Rachel. She says that she doesn't believe in the paranormal but if the ghost of Rachel Parsons is out there then she would release Miranda from the cell. Suddenly her cell lock turns. Miranda pushes the door and she escapes. She goes into Pete's office and looks up the story of Rachel Parsons in the computer. Miranda discovers that Rachel committed suicide. Then as Miranda looks at the security camera she sees Rachel standing in the hallway of Chloe's ward. Miranda worries that something might happen to Chloe so she runs towards Chloe's cell. Chloe's cell has a metal door with only a small window to look through. Miranda looks inside and Chloe is thrown against the door with her face pressed to the window. Miranda bangs on the door and a man's tattoo is shown pressed to the window. It is a tattoo of a woman in flames. Miranda gets frightened and she runs away screaming. The guards catch her and she tells them about Chloe. The guards then bring Miranda back to her cell. Since she has escaped from the glass cell she is placed into a steel mesh walled cell.
At night the ghost of Rachel Parsons appear to her. The ghost is angry and starts throwing Miranda around the room. The security guards see this in the camera but all they see is Miranda throwing herself against the walls. They think she is trying to kill herself. The guards run to her room and open the door. Miranda runs away and they chase her around the mental ward. She goes into the pool room and slips into the pool to hide in the bottom and closes her eyes. The guards search and don't see her so they leave. When she hears them leave Miranda opens her eyes and the ghost is right in front of her. She hysterically swims to the top and keeps running. She ends up underneath the desk of a security guard who once respected her. The guard doesn't reveal that she is there and instead gives her the keys to his car and helps Miranda get away.
Miranda runs to the parking lot, finds the car and starts driving towards her house. Suddenly she looks at the rearview mirror and sees the ghost of Rachel parsons in her back seat. Her car speeds up and Miranda tries to step on the brakes but it won't work. She is speeding now and ahead of her there is a truck that is about to cross her path at the upcoming intersection. She speeds up and misses the truck but she ends up hitting a bunch of pylons instead. When the car finally crashes to a stop Miranda screams at the ghost asking what she wants from her.
Miranda drives to her house and feels a presence overcome her. Suddenly she is reliving the murder of Doug, and watching it from a third person's point of view. She sees her possessed self enter the gate, take an axe from the backyard, enter the house and hit Doug with the axe once. An injured Doug crawls up the stairs, smearing blood all over the floor and the stairs. When they get to the top floor Doug is lying on the floor pleading for Miranda not to hurt him. The possessed Miranda is now coming towards him with the axe. Doug keeps asking her what he did and she is immobile, she just keeps walking towards him. Then she stops, tells him "I love you" , raises the axe and starts slaughtering him. Blood splashes all over the hallway. When the possessed Miranda is done she writes Not Alone on the doors, and takes a bath in a pool of blood.
Miranda watches all of this and screams. She goes into her and Doug's old bedroom and sits down to cry. In the morning, an instinct tells her to visit Willow Creek, which is the place where Doug used to go fishing with his best friend Sheriff Ryan. Miranda comes upon an abandoned cottage with a barn. She goes into the barn and looks around. Something comes at her and she screams but it is only a bird. She doesn't find anything so she decides to leave. Just then, she notices the box of a digital video camera on the floor. She examines it and notices a latch on the floor which opens to a basement. Miranda climbs down the stairs and sees a room with a bed and a video camera in front of it. There is also a box on the side filled with medication that they use in the mental institute to sedate patients. The bed has blood stains on it as if someone was butchered on it. There are also chains and shackles on the bed. Miranda goes to look at the video camera and rewinds the tape. When she watches it she is shocked to see a girl lying on the bed with her wrists chained to the bed posts. Her whole body has cuts and she is naked. Then the video reveals Doug coming to the bed, kissing her and then choking her. Doug then comes up to the camera and says "It's good to be god."
Miranda now hears a noise from upstairs and someone is coming down the basement. She grabs a knife and when someone comes towards her she almost stabs him. It's a police officer. He tells her to drop her knife. She says only if he drops his gun. Suddenly a pair of bloody arms come from around Miranda and starts choking her. She detangles herself from the arms. Then, Miranda and the police officer discover that it is a girl pleading for help to get her out of there.
The girl is rescued and they find out that she had been missing for quite some time. Sheriff Ryan goes to the mental ward and is upset that Miranda escaped. He starts accusing them of having a faulty system. He says she could have harmed somebody. Pete points out that she didn't, and instead she saved a life.
Miranda discusses the tattoo of the burning woman with Pete and she realizes that it is starting to get clear to her now. The ghost of Rachel Parsons came to her to reveal to her what her husband Doug has been doing. The slashmarks on her arm Not Alone means that Rachel was not alone, she wasn't the only victim. Rachel wanted Miranda to help the other victim. Miranda figures that Not Alone could also mean that Doug was not alone in his crimes, that he probably had an accomplice. Later on Miranda tells all of this to Sheriff Ryan because since he is Doug's best friend he may know more about it.
Sheriff Ryan rushes to the mental ward to visit Miranda and talk more about this. Miranda tells Sheriff Ryan that there was an accomplice but she can't figure out who. She also tells him about the tattoo of a burning woman. Miranda mentions that she'd discussed this with Pete and Sheriff Ryan seems to be shocked that she'd told Pete about it. They sit down together and try to figure out who the accomplice could be. Sheriff Ryan tells her that since she is a psychiatrist she might have an idea of what kind of person the accomplice would be. Miranda tells him her hypothesis, which is that the accomplice grew up in a home without a father so he grew over dependently on his mother to the point where he was obsessed with his mother. She tells him that he must be someone who has difficulty finding and staying in relationships and so sex becomes a game for him where he would want to take control and execute all of his fantasies. She says he is a highly organized person who can seem very normal and proper on the outside, yet inside he has severe sadistic tendencies that he needs to fulfill. Sheriff Ryan is getting nervous now and he mentions to her that this must be somebody who would be desperate enough to cover his tracks. Miranda mentions that he's also probably desperate enough that he would come talk to her.
Suddenly Sheriff Ryan jumps at Miranda and starts choking her. The ghost of Rachel then appears and turns on some gas and lets them out of the cell. Sheriff Ryan is now chasing Miranda around the mental ward with a gun. She goes into an office and he follows her. Miranda is hiding under a desk and as Sheriff Ryan searches for her he sadistically explains to her why he and Doug committed the crimes that they did. He says that since they were young they had intense sexual fantasies. Doug even killed someone when he was only 15 years old. When they were in college they used to rape a lot of women and then murder them. They stopped for a while until they saw Dr. Phil Parson's daughter, Rachel. They said they just couldn't leave her alone so they kidnapped her and brought her to the barn, which is Doug and Miranda's property. The fact that they were well respected doctors in the community was a perfect cover up. No one would ever think of searching their barn. Sheriff Ryan continues to talk about how they were addicted to raping young girls.
Sheriff Ryan starts firing shots all over the office where Miranda is hiding. Then he looks up and sees a vision of Miranda standing on the other side of the glass. He approaches her, but it's not Miranda, it is Rachel making Sheriff Ryan have illusions. Rachel then reveals herself to Sheriff Ryan and he is bewildered saying it cannot be, because she is dead. The gas that Rachel turned on earlier has now filled the room. Sheriff Ryan aims at the ghost and fires a shot at her and the room bursts into flames. Ryan catches fire and screams. He turns around and Miranda is there holding a gun. She fires a shot at his forehead killing him.
The movie closes with Miranda and Chloe walking on a street. They have been released from the mental institute for a while now, and have become friends. Miranda tells Chloe that she has put "those days" in her past and closed the door. They say goodbye. Miranda is alone now and she walks by a post with a poster of a missing boy on it. She disregards the poster. Suddenly ahead of her she sees a boy standing in the middle of the road. It is the same boy from the poster but she does not realize this. A bus is coming from behind him ready to hit him. Miranda is about to try to save the boy and he disappears. She takes a moment to compose herself and she keeps walking. Then there is a close up of the poster of the missing boy. Screen dims. The end.