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At the start of this issue, Spider-Man is driving the Spider-Mobile for the first time in months, in the hope that it could help him find the Jackal. He's soon chased by some police, but manages to get away. However, in his escape he drives down an alley filled with smoke, only to find that it somehow changes to a pier as he is halfway along it. The Spider-Mobile falls into the river and is lost, although Spider-Man manages to get out. Spider-Man then heads to Empire State University, although he has trouble staying awake. After being told by Professor Warren that he has to attend class more, Mary Jane arrives, and Peter goes off with her.
Meanwhile, at J. Jonah Jameson's club, Jonah receives a mysterious phone call. The person on the other end tells Jonah that he's made contact. Jonah then hangs up, looking very pleased. While this is happening, Spider-Man is swinging around town, when some mysterious mist circles around him. This disorients him enough that he falls, and even though he doesn't die, he does almost dislocate his shoulder in saving himself.
Spider-Man is then approached by the creator of the mysterious mist, who turns out to be Mysterio. Mysterio fights Spider-Man with a different fighting style from their previous battles, before running off. Upon Spider-Man following him, he finds a large group of his villains alongside Mysterio. Spider-Man realizes that they're only illusions, but psyches out during the fight and punches a wall with his fists so badly that they are scarred and badly damaged. Mysterio then taunts Spider-Man that he will die soon, before disappearing. Spider-Man then changes to Peter Parker and visits the Daily Bugle, but upon telling them about Mysterio, Ned Leeds tells Peter that Mysterio died in prison almost a year ago.