Wade Wilson, a former special forcesoperative now working as a a mercenary in New York City, meets an escort named Vanessa at a local bar, forming a one-night stand into a relationship. After a year Wilson proposes to Vanessa; he is affected byterminal cancer on the same night the two become engaged. Despite Vanessa's love for him, he detests the thought of her watching him waste away, and he leaves.
Jared, a recruiter from a covert organization, approaches Wilson promising abilities that will cure Wilson's cancer. Wilson at first rebuffs his offer and mocks him with pedophile jokes, but soon reconsiders and enters the proposed treatment program. He is taken to a remote laboratory where he meets Ajax and Angel Dust, and instantly resents them. Ajax injects a mutation-activating serum into Wilson and subjects him to daily torture to activate it, without success. During this time, in spite of his continuing agony, Wilson maintains his incessant sarcasm, and teases Ajax about his real name, Francis. Annoyed, Ajax asphyxiates him in an oxygen chamber, developing an accelerated healing factor that cures him, but causes disfigurement throughout his body. Wilson finds a way to destroy the lab and escapes his confines. He battles Ajax, but relents when Ajax promises a cure. Ajax then impales him with arebar, and leaves him for dead.
Wilson survives and attempts to return to Vanessa, but is unable to approach her, afraid of her reaction to his disfigurement. After consulting his best friend Weasel, Wilson begins the task of tracking down Ajax to get the cure. He becomes a masked vigilante, adopts the alter-ego "Deadpool", and resides with an elderly blind woman, Al. Following a string of leads, Wilson tracks Ajax to a convoy on an expressway. He executes the numerous convoy guards and corners Ajax, demanding the cure, but is interrupted by Colossus and Negasonic Teenage Warhead, who attempt to recruit Wilson into the X-Men; Ajax escapes. Angered, Wilson abandons them, cutting off his own hand in the process, knowing it will regenerate overnight.
Ajax and Angel Dust go to Weasel's bar and learn about Vanessa. Weasel warns Wilson that she is in danger, and both go to Vanessa's strip club job. Ajax and Angel Dust lure Vanessa outside to be kidnapped, telling Wilson to meet at a decommissioned helicarrier in a scrapyard. Wilson persuades Colossus and Negasonic to help, travelling to the scrapyard and battle with Ajax, Angel Dust, and their team of mercenaries. As Colossus and Negasonic battle Angel Dust, Wilson kills the mercenaries and a violent hand-to-hand combat takes place between Wilson and Ajax atop the helicarrier. During the battle, Negasonic accidentally destroys the equipment stabilizing the helicarrier, tipping it over and scattering Ajax and Wilson. As Colossus carries Negasonic and Angel to safety, Wilson saves Vanessa and injures Ajax. Wilson demands his cure: Ajax laughs and reveals there is none, and Wilson kills him in response, despite the attempts of Colossus to dissuade him. Vanessa, angry with Wilson for abandoning her, reconciles when she learns why he stopped seeing her, and they share a kiss as the movie ends.
In a post-credits scene, Wilson tells the audience that the movie is over and then announces the sequel featuringCable.
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