After fighting organized crime as the wisecracking mercenary Deadpool for two years, Wade Wilson fails to kill one of his targets on his anniversary with his girlfriend, Vanessa. That night, after the pair decides to start a family together, the target tracks Wade down and inadvertently kills Vanessa. Wade then kills him in revenge. Blaming himself for Vanessa's death, he attempts to die by suicide six weeks later by blowing himself up. Wade has a vision of her in the afterlife, but remains alive due to his healing abilities, and his body is restored by Colossus. Wade is left with only a Skee-Ball token, an anniversary gift, as a final memento of Vanessa.
Recovering at the X-Mansion, Wade reluctantly agrees to join the X-Men because he believes Vanessa would have wanted him to. He, Colossus, and Negasonic Teenage Warhead respond to a standoff between authorities and the unstable young mutant Russell Collins at an orphanage owned by the Essex Corporation, labeled a "Mutant Re-education Center". Realizing that Russell has been abused by the orphanage staff, Deadpool kills one of the staff members before being restrained by Colossus, and both Wade and Russell are arrested. Fitted with power-suppressing collars, they are taken to the Ice Box, an isolated prison for mutant criminals. Meanwhile, Cable, a cybernetic soldier from the future, travels back in time to kill Russell.
Cable storms the Ice Box and attacks Russell. Wade, whose collar breaks in the ensuing melee, attempts to protect Russell. After Cable takes Vanessa's token, Wade forces himself and Cable out of the prison, but not before Russell overhears Wade denying that he cares for the young mutant. Near death again, Wade has another vision of Vanessa in which she convinces him to help Russell. Deadpool organizes a team called X-Force to free Russell from a prison-transfer convoy and protect him from Cable. The team launches its assault on the convoy by parachute, but all members die during the landing except for Deadpool and the lucky Domino. While a fight with Cable distracts them, Russell frees fellow inmate Juggernaut, who agrees to help him kill the abusive orphanage headmaster. Juggernaut destroys the convoy, rips Deadpool in half, and escapes alongside Russell.
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