After his family were killed, Frank Castle became a vigilante called the "Punisher", targeting those who prey on innocent lives, such as gangs. His associate "Microchip" tipped him off on taking crimes taking place around New York City, and the Punisher would then arrive at the scene of the crime to stop it. Castle's vigilante career resulted in him being wanted by the FBI and CIA for questioning in the disappearances of various crime figures.

When J. Jonah Jameson made a news broadcast announcing that Spider-Man had kidnapped Michael Morbius from his hospital room (Morbius was really a vampire-like creature and had fled), the Punisher set out to eliminate Spider-Man for his alleged menacing ways. Spider-Man initially gained the upper hand and escaped, but Punisher tracked him and fired a rocket launcher at him, resulting in him falling through the roof of a building. As Punisher entered the building, Spider-Man's mutation disease caused him to mutate into a gigantic humanoid spider.

The Punisher continued in pursuit of a mutated Spider-Man, but was ambushed by Sergei Kravinoff, whose partner was working on a cure for Spider-Man's mutation. Sergei tried to persuade Punisher to refrain from harming Spider-Man because he was innocent and a victim to a mutation disease, but Punisher insisted on his mission. However, he eventually agreed to work together with Sergei, and with their help Mariah Crawford gave Spider-Man a serum to return him to normal.

While visiting his family's gravestones, Frank encountered Anna Watson, who explained to him how her niece Mary Jane Watson had mysteriously disappeared, and how she suspected her niece's boyfriend and friend's nephew Peter Parker of being involved. He agreed to investigate, and after doing so came to the conclusion that Peter Parker (who was actually Spider-Man) was the Green Goblin. While being confronted by the Punisher, Peter fled on the goblin's glider, leading Frank to believe his suspicions were correct. However, it later became clear to him that Peter was not the goblin, since the Green Goblin at that point was Harry Osborn, who was captured by the Punisher. Mary Jane suddenly reappeared to Peter while he was being questioned by the Punisher, who then returned her to her aunt.