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Two years after the first movie, Deadpool has become an international hitman who only kills bad guys. On his anniversary with Vanessa, he lets a target get away. That night, Wade and Vanessa decide to start a family. Minutes later, the criminal storms the apartment looking for Wade and kills Vanessa. Wade gets revenge, but he is shattered.
Six weeks later, he tries to kill himself by blowing himself up. As always, he grows back. Colossus gathers the pieces and brings him to the X-Mansion, where Wade becomes a trainee. On his first mission, at an orphanage called Essex surrounded by police, he meets Russell, a mutant kid who shoots fire from his hands and says the headmaster abuses him. Wade realizes it's true, kills a staff member, and both end up in the Ice Box, a mutant prison with collars that shut off powers.
Cable arrives from the future, a soldier with a bionic arm. In his time, Russell grows into a killer who murders Cable's wife and daughter, and he has come back to kill the boy first. Cable breaks into the prison, but Wade gets in his way. In the fight, Wade gets thrown clear, and Russell, hurt by him, bonds with another inmate, Juggernaut. To save the kid, Wade puts together X-Force through a job ad. During the parachute drop on the prison convoy, almost everyone dies in ridiculous ways. Only Wade and Domino are left, and her absurd luck takes care of the rest. Russell frees Juggernaut and they head to the orphanage to kill the headmaster.
Cable offers a truce: Wade gets one shot at talking the kid down. If he fails, Cable pulls the trigger. At the orphanage, Juggernaut beats everyone until Colossus shows up and takes him down. Cable fires at Russell, and Wade, wearing a collar that blocks his healing, jumps in front of the bullet. Dying, he tells Russell there is still time to be a good person. The kid gives up on killing the headmaster, and Cable's future changes.
Cable uses the last charge on his time device to jump back a few seconds and places the token Vanessa gave Wade right where the bullet hits. Wade survives. Dopinder, the cab driver, runs over the orphanage headmaster. Cable decides to stay in the present, knowing his family will be safe in the future. In the post-credits scenes, Negasonic and Yukio fix the device, and Wade goes back in time to save Vanessa and his teammate Peter, plus clean up a few embarrassing moments from his own career.