Wade Wilson ambushes Ajax and his troops on the highway. In the beginning, when Wilson first encountered Vanessa, a prostitute, he had been a free-lance mercenary since being dishonorably discharged from the Canadian Special Forces. They fall in love and accept his marriage proposal a year later. Wilson, however, eventually learns that he has terminal cancer. Wilson is approached by a mysterious recruiter who offers him an experimental cancer therapy. He abruptly departs from Vanessa so that she won't have to witness his passing.

He is transported to Ajax and Angel Dust's laboratory, where he is injected with a serum meant to activate dormant mutant genes in his body. Wilson is subjected to days of torture in an attempt to start whatever mutations he may have. When Wilson learns that Ajax's real name is Francis and makes fun of him for it, Ajax locks Wilson in a hypobaric chamber over the weekend, where he periodically approaches the point of asphyxiation. This ultimately activates a regenerative healing component, which fights Wilson's cancer but leaves him deformed with burn-like scars all over his body. When informed that his deformity may be fixed, he backs off and assaults Ajax after escaping the chamber. Amid the turmoil, Ajax subdues Wilson and abandons him in the now-burning laboratory.

Wilson survives thanks to his new healing skills and searches for Vanessa. He doesn't tell her he's alive because he's afraid she'll reject his new appearance. After speaking with his best friend, Weasel, Wilson decides to track down Ajax for the cure. As a result of Weasel scooping him out of a lifeless pool, he takes on the vigilante persona of "Deadpool" and settles at the house of Al, an elderly blind woman. Over the next year, he interrogates and murders many of Ajax's accomplices until one, the recruiter, exposes Ajax's location. This information enables Deadpool to carry out the ambush. He murders all of Ajax's goons, subdues Ajax, and demands the cure, but he is interrupted by the X-Man Colossus and his apprentice, Negasonic Teenage Warhead. Colossus tries to persuade Deadpool to change his ways and join the X-Men, but Deadpool refuses. Ajax takes advantage of the diversion and flees with Angel Dust. They then go to Weasel's tavern, where Ajax learns about Vanessa.

Vanessa is kidnapped by Ajax and taken to a scrapyard aboard a disused helicarrier. In reaction, Deadpool persuades Colossus and Negasonic to assist him in reclaiming her. While Deadpool fights his way to Ajax, they are attacked by Angel Dust and a bunch of Ajax's troops. During the combat, Negasonic mistakenly damages the helicarrier's stabilizing equipment. As the ship falls around them, Deadpool protects Vanessa while Colossus transports Negasonic and Angel Dust to safety. Ajax attacks Deadpool once more, but this time he is outmatched. He reveals that the treatment never existed in the first place, and despite Colossus' pleadings, Deadpool murders Ajax, promising Colossus that he will strive to be more heroic in the future.