The movie opens with Osborne Cox (John Malkovich), a CIA Analyst, being called into a meeting by his superiors. In the meeting they tell him that he is being demoted to a position in the state department due to his drinking problem. Osborne is furious and believes that the entire thing is office politics and quits shortly afterwards. Later on, he informs his wife Katie (Tilda Swinton) that he has quit his job because he is interested in doing other things. When Katie presses him for what exactly “other things” mean, Osborne says that he will write a memoir of his of CIA experiences. It is shown that Osborne and Katie have been having marital problems, especially when they cannot get along at a party that they are throwing that also includes paranoid treasury agent Harry Pfarrer (George Clooney) and his wife Sandy, a famous children's author. During the party is it revealed that Harry and Katie are having an affair.
The next scene shows Linda Litzke (Frances McDormand) at a doctors office talking about cosmetic surgery and all the things she would like to improve with her body. She works at a gym called Hard Bodies and she tries to use her medical plan to pay for the surgeries, but is denied. Her boss Ted (Richard Jenkins) tries to tell her that she looks great, obviously having feelings for her, and does not need the surgery. Linda is completely oblivious to Ted's feelings though and still thinks she needs the surgery to look attractive. In her spare time, Linda and her co-worker Chad Feldheimer (Brad Pitt) look at potential suitors for Linda on an online dating site. After looking at several different men, Linda agrees to meet with one man. But after having sex with him, he turns out to be married.
Katie decides to divorce Osborne. She goes to a divorce attorney who advises her to go onto his computer and copy of all of the information on his hard drive, so they can get copies of whatever financial data he has on there so he cannot hide assets. Katie copies the hard drive while Osborne is getting drunk at a college reunion, she also copies the details of his memoir onto a disk. Katie gives the disk to her lawyer, who passes it off to his assistant who loses it at Hard Bodies, where is it discovered by Chad.
Chad and Linda look and see everything that is on the disk. Most of it is written in code, but Chad takes it to a friend of his that tells him that it has government information on it. Linda and Chad figure it out it belongs to Osborne and conspire to black mail him for $50,000 to get the disk back so Linda can pay for her cosmetic surgery. Late at night, they call Osborne and demand money for the disk. After a humorous exchange where Chad keeps repeating the same lines over and over again because he doesn't know what to say ("Is this Oswald Cox?") Osborne sets up a meeting time with Chad.
In the meantime, Osborne is served with divorce papers. Harry's wife goes on a long book tour and, while she is gone, he moves in with Katie. But Harry is also cheating on Katie and using the same online dating site that Linda used earlier. Linda and Harry eventually meet up and go on a date and begin to see each other regularly. Harry even takes Linda to his wife's house to show her what he has been working on in the basement (something he refused to show to his wife earlier): a rocking chair with a dildo placed in the crotch that thrusts upwards every time the chair rocks back and forth. Meanwhile, Harry begins to suspect he is being followed by someone.
Chad and Osborne meet up and Chad asks for the money, but Osborne instead threatens him with jail time and then punches Chad in the face and drives away. Linda and Chad follow him and Linda smashes into the back of Osborne's car to send him a message. Linda then drives to the Russian embassy, with a bloody Chad, to try and sell the disk to the Russians for money. The Russians agree to take a look at the disk, but only after Linda promises to provide the Russians with more information. Chad is wondering how they are going to provide more information when all they had was the disk. Linda then tells him he is going to break into Osborne's house and look for more information.
Chad stakes out Osborne's house and waits for Katie and Harry to leave, Harry only goes for a jog, before he breaks into the house. Harry soon returns though and Chad hides in the closet in the main bedroom. Harry opens the closet and finds a smiling Chad. Harry is so shocked that he immediately shoots Chad point blank in the face. Harry runs down stairs and falls over. Not realizing that Chad is dead, Harry grabs a kitchen knife (he left the gun up in the bedroom) and begins to walk back up stairs. Harry can see Chad's limp legs lying outside the closet still but does not realize that he is dead, so he makes a big dive into the bedroom and grabs his gun and points it at Chad, only to realize that Chad is actually dead. Harry thinks that Chad was a spook looking to kill him.
Cut to CIA headquarters where one of the men who demoted Osborne at the beginning of the movie is talking to his superior officer (J.K. Simmons). Apparently the Russian embassy told them about the disk that Linda gave them and there was an Agent staking out Osborne's house the entire time. The CIA officer then reports that their agent witnessed Harry put Chad's body into the trunk of his car and dump the body into a river. The CIA Superior asks if they fished the body out and when he finds out that they did, he tells them just to burn it and get rid of it anyway and to keep him posted on everything.
Linda has not heard from Chad in several days at this point and is beginning to fear for her life. She becomes even more hysterical when Ted tells her that Osborne came to Hard Bodies earlier in the day looking for her. Linda then goes back to the Russian embassy, who give her back the disk and tell her that nothing worthwhile is on it. Linda then coerces a reluctant Ted into breaking into Osborne's house himself and looking for more information to try to sell.
Meanwhile, things begin to sour between Katie and Harry and Harry walks out on her. Harry then sees the same car outside who was following him throughout the movie. Harry crashes into it and chases the man who was inside of it, he tackles him on the street and demands to know who he is working for. The man responds that he was hired by his wife's lawyer to serve Harry with divorce papers. Harry's wife is having an affair with a weatherman in Seattle and is leaving him. Harry is heartbroken and goes to Linda for support and Linda asks if Harry will use his connections in the government to find her missing friend. They go for a walk and sit down at a park bench and Harry notices someone starring at Linda awkwardly starring at another man sitting at another bench and asks who it is, but she denies knowing the person (it is actually the person Linda slept with earlier in the movie who was married). Harry becomes paranoid and while Linda is talking about finding Chad, Harry realizes that Chad is the same man he killed earlier in the film. Harry then suspects Linda is involved in some kind of operation to arrest him and demands to know who she works for, he then gets up and begins to suspect random people in the park of being involved in a sting operation to get him and runs off.
Meanwhile, Osborne is sitting in his boat and calls his wife and tells her he has the keys to the new locks and picks up a hatchet and walks to his house, wearing only his robe and boxers. Then he uses the hatchet to break into the house and begins to collect personal items, specifically all of his liquor bottles. Osborne then hears something downstairs and grabs a gun that he left in the house and goes into the basement to find Ted copying files from Osborne's computer. Osborne recognizes Ted from Hard Bodies and says that Ted is apart of a “league of morons” and he is putting a stop to this and shoots Ted in the shoulder. Ted manages to hit Osborne with a hole puncher and runs out of the house. Osborne grabs a hammer and follows Ted out of the house and beats him to death in broad day light with the hammer.
The final scene concludes with the CIA Officer talking to his Superior again reporting on the events of everything. Harry was arrested trying to board a flight to Venezuela. The Superior officer says that because there is an extradition treaty with Venezuela to put him on the flight anyway. Ted is dead and his body has been disposed of by the CIA. Osborne was put into a coma after being shot by a CIA Agent, who was still staking out Osborne's house, after killing Ted in broad daylight. Linda has agreed to testify as long as the CIA pays for her cosmetic surgery. The two CIA Agents sit back and agree that they have no idea what they did but they will never ever do it again.
*CUT TO THE CHASE*
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After accidentally shooting Chad (Brad Pitt) in the head, Harry (George Clooney) leaves Mrs. Cox (Tilda Swinton) and storms outside. He confronts his follower who turns out to be a private detective following him for information as his wife is leaving him. Now distraught he destroys the strange dildo chair he has made for his wife and goes to meet Linda (Frances McDormand).
After realizing that Linda was friends with Chad, Harry runs away screaming, thinking she's a member of the CIA, FBI etc.
Linda coerces her coworker (Richard Jenkins) into breaking into Osbourne Cox's (John Malkovich) house, whereupon a drunken Osbourne shoots him and murders him in broad daylight with a hatchet.
A conversation between two CIA agents reveals that Osbourne was shot on the street by another CIA operative who was tailing him, thus rendering him in a coma. Harry is allowed to go to Venezuela after the CIA burns Chad's body. Linda agrees to stay quiet so long as the CIA pays for her elective, cosmetic surgeries.
The disk was full of low level clearance information and Osbourne Cox's personal financial statements.
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