The movie begins with Aaron Cross (Jeremy Renner) under water, in a river at a training site in the middle of snowy mountain region. He swims to the surface, looks at a map, and moves on to his target.
At the same time, in DC, two high-ranking CIA officials are discussing about how Jason Bourne escaped and is active. Bourne has exposed their operation. They need to inform the head of the CIA about the urgency of the situation.
The next morning, they are in the meeting where they discuss that there is another program similar to Treadstone called Outcome, and they are assembling a team to assess the risks of having the program being exposed due to Jason Bourne's escape. The leader of this team is Eric Byer (Edward Norton). One of his team members is admiring Jason Bourne's profile and his ability, but is told-off by Eric, as he needs to focus on the task at hand, assessing the risk.
In the meantime, we see that Aaron has to fight off a pack of wolves on the mountain. He climbs up a very steep mountain after drawing his own blood for a lab test kit, and taking two tablets from a small metal container, one green and one blue.
We see that a similar looking metal container is being kept by another Outcome agent who is being checked up in a lab facility by Dr. Marta Shearing (Rachel Weisz). Each agent is referred to by a number. This agent needs to do a full checkup as per Marta's boss' instructions. At the same time, in the headquarters, Eric is telling the CIA head that Outcome has to be shut down and to save the medicine recipe that they have, and to terminate all of the operatives before it is exposed.
The scene goes to Eric telling another military general that he needs to terminate his Outcome agents in the field. The general argues that doing that will sacrifice years worth of investigation, especially their very important progress in North Korea and in Pakistan. Eric insists that it needs to be done and gives him an order to do so. After the checkup, the soldier is given a yellow pill, instead of the usual blue and green ones. After this, we see that there are agents in various locations such as South Korea and Pakistan, taking the same yellow pill and the agents die shortly after.
Back in the mountain, Aaron has reached his next station and is met by another agent guarding the post. It turns out that Aaron beat the record by two days because he climbs the mountain instead of taking the normal route. In this post, he is supposed to send their blood work taken in specific intervals. Even though he's early, he lies to the other agent that he dropped his medicine container, in order to get more supplies. Initially the other agent doesn't believe him, but gives him the pills anyway, taken from a storage area outside the cabin. After this, they send the bloodwork via drones, to the nearest military post. Aaron and the other agent don't trust each other, but Aaron manages to find out that the other agent has to stay there as a punishment for falling in love. It is implied that Outcome's weakness is the agents' feelings that interrupt with their mission.
Aaron spends the night in the cabin and sees that there were a lot of agents who have stayed there before, including Jason Bourne.
The next morning, Aaron is supposed to continue his journey, but a bad snowstorm is coming, so he decides to stay longer. When assessing the weather, he hears an unusual noise outside. The other agent confirms that there are no drops expected, and they decide to get ready to leave. Aaron goes out first with his kit, and suddenly, the cabin is shot by a missile. The cabin explodes, killing the other agent.
Out in the military base, the soldiers suddenly detect Aaron's signal 15 minutes after the attack, and decide to send the drone back to assess the situation. Aaron quickly covers his stomach area with a metal plate, so that his implanted signaling device is not detected, and waits for the drone to be within sight of his highly enhanced rifle. He manages to shoot the drone down. Soon after that, he decides to take the detector out of his stomach. At the same time, the base gets the signal back and decides to send another missile. While Aaron his doing his mini-operation, a pack of wolves come and surround him. Aaron traps one of them, and scares the rest with his gun shots. He wrestles with the caught wolf and forces the detector into its mouth. The missile shoots the target successfully and confirms it dead, not knowing that it has shot the wolf and not Aaron. He makes his way to a small airport, steals one of the planes, and flies back to the city. However, at this point of time, he only has two blue and green pills left. He needs to get new meds; otherwise he will get the withdrawal symptoms and may not make it. Aaron has flashbacks to the time when he is in the field with Eric, where he is told that Outcome program is morally indefensible but necessary to defend the country.
In the meantime, Marta's colleague starts to behave in a weird manner. Eventually, he locks all the scientists in the lab room and shoots them one by one. Everyone is killed except Marta, but she survives by running to a room, locks herself in and stalls the killer to buy time. Eventually security guards gain access to the room, and her colleague kills himself.
Marta is very shaken, and we see her back at her home, preparing to leave the country. CIA agents visit her, claiming to be the CIA psychologist who needs to assess her state of mind before allowing her trip out of the country. Suddenly, the agents start to restrain her and try to force her kill herself with her own gun. Right at this time, Aaron appears and saves her, and helps her kill all four agents, and burn down her house to remove evidence and stall the CIA investigation.
Marta and Aaron escape together, and Aaron grills Marta on the location of the blue and green pills. From here we know that Marta only does the lab analysis and decides on the dosage, without access to the pills. She also does not know of Aaron's real name as each agent is referred to only by numbers, even though he has been going to the same lab facility for 4 years, with 13 visits in total. He finds out that all agents don't need any green pills anymore since their body has the permanent resistance already starting from 8 months back, when a live virus was injected into their bodies. Marta wants to leave, but Aaron tells her that the govt. is shutting down the program and made his colleague kill all the scientists and that she will soon be killed too if she tries to go to the media or police. So, Marta decides to help Aaron off the blue pill by injecting a live virus so that he doesn't need the blue pills at all. For this, they need to go to Manila, Philippines, where the live virus cultures are.
Marta and Aaron spend the night in a motel, where Aaron makes Marta's fake passport and identity, as Jane Monroe.
Back at Marta's home, the CIA is having a hard time putting the pieces together as the house is badly burnt and they need time to identify the burn victims. However, they found out that Marta escaped but have no idea how or who is helping her.
The next day, Marta and Aaron go separate ways in the airport towards the same flight, with Aaron giving Marta instructions on what to do, and where to go. They safely board the plane, and reach Manila without anyone detecting them. During the flight, Aaron creates a fake ID card for himself as the company employee, Dr. Karl. When they reach the lab's factory compound, nobody was informed of their visit. Luckily Marta recognizes the security guard, Joseph, and Aaron manages to convince the guards such that they are given access into the lab. While Marta is injecting Aaron with the live cultures, we see scenes of Eric and his team figuring out that Aaron has been involved in helping Marta.
They instruct the factory to be shut down, and locked down. At the same time, guards have been sent to confront Aaron. He easily subdues them and realizes that their cover is blown.
They escape by creating chaos in the factory, and running out of the factory among other hundreds of factory employees.
At this time, Eric activates another assassin stationed in Bangkok, two hours away from Manila, which is part of a new program where the assassin has a very high physical capability, without Treadstone's inconsistency and Outcome's emotional feelings. The program was started by Eric, without CIA officials' approval. They have no other options, and have to use the assassin.
In Manila, the virus is taking effect, and Aaron is too sick to walk, so they have to spend the night in a rented room in the middle of the housing area near the factory. Before passing out, Aaron asks Marta to take his money and passports, and escape, rather than risking her life staying with him, but she refuses. At night, he has nightmares from the time when he was recruited to join Outcome. At that time, he was badly injured while surviving an attack during a military mission in Iraq.
The next morning, Aaron wakes up, feeling much better than the night before. He is relieved to have survived the night and not needing the pills anymore. He hangs his metal container on the mirror side. Marta is away buying medicine to help him recuperate when she realizes that the place is surrounded by police and local army teams. She alerts Aaron by screaming from the streets, causing the police to chase her down the alleys. With Marta's warning, Aaron escapes through the roof, and he tries to track Marta down to save her from the local police.
At this time, the assassin from Bangkok arrives on scene and starts chasing after Aaron, along with the police. After a rooftop chase scene, Aaron manages to shake all the police, and regroup with Marta. Shortly after, he realizes that the assassin is trying to kill both of them. Aaron steals a police motorcycle, and there is a long chase scene, along with the assassin in the police car. They try to escape in the middle of a horrible Manila traffic jam. After a while, they escape from the police and manage to shoot the assassin in the back, but Aaron got shot in the shoulder, as a result. He starts to get weaker and needs to escape, but the assassin gets back up and starts chasing them again.
During the high speed pursuit, in the middle of a deserted parking structure, Marta tries to fight back and manages to kick the assassin from the bike, killing him. They fall from the bike as a result, and they ask for help from local man who happens to be there with his son.
The CIA headquarters sees the room where Aaron and Marta spent the night, and see that Aaron wrote 'No More' on the mirror, implying that he doesn't want to be involved in the program, and he doesn't depend on the CIA to provide the pills anymore.
The last scene shows Aaron as a passenger on the local man's boat in the middle of East Asian water. Aaron is studying maps, with Marta at his side.
At the same time, we see that the CIA is trying to cover up Treadstone after Jason's exposé, and is suing Pamela Landy (Joan Allen) as the scapegoat.
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