Having broken out of prison, Dr. Octopus gathers Mysterio, Electro, Kraven the Hunter, the Vulture and Sandman to get revenge against Spider-Man as the Sinister Six. Meanwhile, Spider-Man has once more found that his spider powers have faded and has to exercise more caution getting back home, lest someone take advantage of his lost powers to find out his secret identity. As Peter wanders the city lost in thought over all the stress caused because of his Spider-Man identity, he doesn't go to school. This prompts the school to call his Aunt May. Worried about Peter, she goes to Betty Brant for help, and they, in turn, see if J. Jonah Jameson has seen Peter recently. This makes them a target for the Sinister Six, who have decided to use Betty Brant as bait to lure Spider-Man, and so they kidnap both Betty and Aunt May. Peter arrives at the Bugle just in time to see the Vulture delivering a message to Jameson. The Vulture tells him that the Sinister Six has gone to six different locations and at each location has a clue to the whereabouts of Betty and May. While super-heroes all over the city try to find Spider-Man, Peter decides that powers or no powers, he's going to save his Aunt May and Betty from his enemies. At the first location, the local power plant owned by Stark Industries, Peter faces Electro. During the fight, he realizes that his powers have returned. He easily defeats Electro and learns the next location. When Iron Man arrives to offer help, Spider-Man refuses. His next fight is with Kraven the Hunter who attacks Spider-Man in Central Park with three tigers. Spider-Man easily fights off the attackers and secures the next clue. Along the way, the Human Torch offers help, but once again, Spider-Man refuses. His next location is controlled by Mysterio, who sends androids based on the X-Men to attack the wall-crawler. Spider-Man easily defeats the androids and Mysterio. The next clue is set ablaze, but Spider-Man recovers its contents with his web-fluid. His next battle is against Sandman, sealed in an airless room. Spider-Man defeats Sandman with his superior lung capacity. Next, he battles the Vulture high over the city and defeats him as well, gaining the location of Dr. Octopus, who has been holding Betty and May hostage. May, completely oblivious to her situation, believes they are Octavius' houseguests. Spider-Man battles Octopus and his mechanical arms. Their fight takes them to a giant fishbowl, where Octopus battles Spider-Man in his "natural habitat." Spider-Man defeats Octopus by filling the tank with his webbing and tangling Octavius up. Spider-Man frees Aunt May and Betty Brant. Returning to his civilian guise, he meets up with them as Peter Parker. Aunt May remains upset with Peter over his skipping class. Jameson is once more made a fool, when he has to publish a story about how heroic Spider-Man is, and as for the Sinister Six? Forced to share a prison cell, the villains squabble among themselves.