The Carnage symbiote was recreated by Michael Morbius under Crossbones' orders. After being injected with a serum with vampire bat DNA in it by Doctor Octopus, Morbius retaliates by throwing the symbiote on Doc Ock, turning into Carnage-Ock. Spider-Man and Flash Thompson were able to use a sound device on the symbiote which not only removed it from Doctor Octopus, but also neutralized the nanites that changed Doctor Octopus' appearance. The Carnage symbiote then forms itself to its familiar form as it plans to cause chaos. He does this by causing Spider-Man and Agent Venom to trick it into exploding so that the civilians below can become infected by the fragments of the Carnage symbiote.
Carnage fragments possess every civilian in Manhattan including J. Jonah Jameson, the Hulk and Shriek. Spider-Man had to work with Captain America, Agent Venom, Iron Fist, and Cloak and Dagger to fight them even when some Carnage-possessed civilians awaken Harry Osborn from his coma enough to be Anti-Venom again. Upon getting control of the Anti-Venom, Harry sacrifices its powers to undo Carnage's control on the civilians.
The Carnage remains reassemble into one giant Carnage as it envelopes Midtown High. While fighting passed the Mini-Carnages, Spider-Man, Agent Venom, and Harry Osborn in the American Son armor find that Mary Jane Watson has been transformed into the Carnage Queen as the mutated Morbius uses a mind-control device on her head. Morbius and Crossbones later further their plans to use the deactivated missiles confiscated by S.H.I.E.L.D. below Midtown High to send Carnage drones to every city in the world. Upon Spider-Man breaking the mind-control device, the Carnage Queen fends off Morbius and Crossbones as Spider-Man, Agent Venom, and Patrioteer reveal their identities to Mary Jane to break her free from the Carnage symbiote. What they don't know is that some residue of Carnage is still in Mary Jane.