The story begins with Electro waking up in a hospital and being questioned by F.B.I. agents. They inform him that he has been unconscious for three weeks, and ask him what he was doing found in the basement of Fisk Towers. Electro remembers his fight with Spider-Man and how he was soundly defeated, and then blows up the hospital room with his powers, killing everyone in it. He then flies out, but is quickly arrested by Captain America, Iron Man, and Black Widow.
We then shift over to a S.H.I.E.L.D. holding facility where five of Spider-Man's villains are engaged in a group-therapy session organized by Hank Pym. Doctor Octopus expresses regret for his murderous actions, Electro questions what the charge is for his imprisonment, Sandman remains unrepentant, and Osborn refuses to speak, telling Pym only to 'bring him his boy'.
When Pym declines, Osborn then asks why he's wearing a genetic-suppression collar, because he needed Oz for his powers. Similarly, he asks why Octavius needs one too, since Octopus' arms were confiscated. But before Pym can answer, Nick Fury appears and tells them all that they are all detained for illegal genetic manipulation, and that they can either rehabilitate or rot in prison.
The story then sidesteps to an interview with Kraven the Hunter on a talk show, where they're showing past footage of his loss against Spider-Man. Kraven tells the host that he has returned new and improved to take down Spider-Man, but as he leaves the studio with his PR rep, they are stopped by the Ultimates. Captain America informs him that they are planning to arrest him on accounts of genetic tampering. Kraven attempts to make a run for it, but Hawkeye easily stops him with an arrow, and the team brings him in.
Kraven is then held by several S.H.I.E.L.D. agents in the earlier holding facility, and Agent Sharon Carter briefs him on his situation. Kraven tries to trigger his transformation, but his collar returns him to his human state, and he is thrown in with the rest of Spider-Man's villains. In there, Osborn wonders why Fury would 'put all six of us in here together.' When Octavius tells him there are only five of them, Osborn says that 'there will be six'.
The second chapter begins with another group therapy session where Pym shows footage of Osborn's fight with Spider-Man, and asks Osborn how he feels. Osborn refuses to comment, and claims that all Pym wants is to get him to reveal the Oz formulas, but then Pym reveals that they already have them. In rage, Osborn triggers his Goblin transformation, but the collar, mixed with tranquilizers and Pym using his Giant-Man powers, are able to bring Norman down.
Six weeks later, Agent Carter brings back the heavily-sedated Norman, and Octavius tells the guards that he's ready to talk. He then tells the scientists at the holding facility that he is willing to help them in whatever way they want, and that he wants to help contribute something as a man of science, rather than a murderer.
In the Triskelion, the entire team gathers together with Fury as he shows them a clip of Dr. Octopus rampaging through New York. Wasp comments that she wrote one of her Doctorates on him and worshiped the man, and Fury informs them that he has been imprisoned with other illegal genetic mutations. He then tells them that Pym has been working with them to stabilize their systems so they can be put on trial. Fury then says that Octopus has offered his cooperation and expertise, and asks the team what they think of that.
When Thor questions him as to why they're being consulted, Fury explains that if it all goes wrong, it's the Ultimates that will be called in to clean up the mess. Captain America then asks Fury if these mutations were all a result of Super-Soldier experiments that Fury commissioned to recreate him, and Fury concedes. Cap then leaves the meeting in silent anger.
Back at the holding facility, Octavius' help has been accepted, and scientists show him his arms, claiming that it's revolutionary apparatus. Octavius then voices a theory he has, that perhaps the arms were connected to him mentally, and that the Oz formula activated some latent low-level telepathy he might have had. He then murders all of the people in the room with his tentacles before disabling the entire facility's power. The rest of the incarcerated villains break free, and Osborn and Octopus make a mutual pact to bring down Fury. The five of them then escape the facility, and Osborn says he'll be looking for his 'son' - Peter.
In the Triskelion, Fury gets an alarm that the holding facility has been compromised. He puts out an alert to the Ultimates, and the team arrives at the facility to investigate. Iron Man lands and enters the building, and finds three survivors out of thirty-eight personnel. He also finds an unconscious Hank Pym, and Wasp quickly flies to her estranged husband in panic.
Back at the Triskelion's briefing room, Fury is showing footage from the holding facility of the villains breaking out. He then states that containment is their priority, and that S.H.I.E.L.D. satellites can only detect them when they trigger their genetic transformations. Fury abruptly realizes that the villains might be going for Peter Parker.
In Queens, Peter is excused from his class by Agent Clay Quartermain, and brought to the Triskelion. There he meets the Ultimates, who are surprised at his age, and Fury tells him that his villains have escaped. Fury assures him that they have personnel surveying both Aunt May and Mary Jane, and then tells him that their agents will follow them discreetly, but asks if he would rather 'come clean' with his aunt. When Peter tries to call Mary Jane to warn her about Osborn, Fury loses his temper.
At the White House, the chief of staff gets a call from Osborn, and then goes on to meet with the President of the United States.
The five escaped villains crash in the Kingpin's summer home in the Hamptons, and Octopus uses some technology taken from the facility to create a secure line. Osborn then makes a call to the White House.
Later, Fury is called in for a meeting with the President, who is enraged that Osborn has called his home. Apparently, Osborn has demanded that they return to him his company, his money, his son, and amnesty to the rest of the villains or he'll leak all of the information about Fury's illegal super-villain 'concentration camp'. Osborn claims that Kraven's TV crew is following them and recording their every move, and that they'll leak their story to the media unless their demands are met. The President is furious that his entire administration is held for ransom, and screams at Fury to find the villains. As Fury leaves the Oval Office, he gets a call from Osborn, who mocks him.
Back at the Hamptons, Osborn tells the rest of the villains that he plans to bring down Nick Fury. He says that any of them are welcome to join, or welcome to leave. But he guarantees to them that his plan will work, and that they will be paid off by the government in exchange for silence. Each man willingly joins, and then Osborn reveals that his claim about Kraven's TV crew was a bluff, and intended as a distraction.
In New York, the Ultimates detain Kraven's TV crew and realize that it was just a ploy by Osborn to occupy them; the crew were never recording the villains at all. Osborn just wanted the heroes out of the way. Meanwhile, Octavius has used this distraction to download the security codes for the Triskelion.
At the Triskelion, Peter gives a call to Aunt May, when the Ultimates' base of operations is suddenly hacked into by Doctor Octopus. Fury orders an emergency shutdown of the base, but the villains appear in the compound with an ambush, and successfully abduct Peter.
In New York, Aunt May is brought in by Black Widow and some S.H.I.E.L.D. agents for her own safety. Widow tells her that Osborn is on the loose, and that he has made threatening remarks on Peter. At the Triskelion, Fury is surveying the damage done by the ambush, and Quartermain informs the General that Banner was asleep during the attack and has been sedated. He also notes that Magneto's oxygen supply was cut during his ambush, and that they've sedated him as well. The Ultimates return to base.
In an unknown Oscorp warehouse, Peter awakes, having been tied to a chair, and sees his five rogues looking down at him. When Kraven realizes that Spider-Man is just a teen, he flies into a rage and tries to kill him, but Octopus and Osborn restrain him. Norman then starts calling Peter 'his boy', and tells him that Peter is his greatest creation, and his true son. He then says that he wants to show him how the world truly is. Peter breaks free of his ropes in fury, calling Norman insane, but then Osborn quietly tells Peter that he will murder all of Spider-Man's friends and family if he does not comply. Spider-Man surrenders.
Back at the Triskelion, Captain America and Fury speak, and Cap expresses his anger - noting that all of this trouble was a direct result of the Super-Soldier experiments that Fury commissioned. He then states that these half-mutated freaks are all that they have to showed for years of experimentation. But then Fury abruptly realizes what Osborn's true plan is.
The White House is attacked by the Ultimate Six - six of them including Peter. But a S.H.I.E.L.D. Helicarrier arrives with the Ultimates, and a showdown begins.
On the lawn of the White House, a battle has broken out between the Six and the Ultimates. Captain America tackles the Green Goblin, Wasp and Hawkeye attack Dr. Octopus, Thor fights Electro, Black Widow matches blows with Kraven, and Iron Man goes up against Sandman. As the chaotic battle rages on, Peter stands in the center of it all, completely shell-shocked. Goblin grabs Peter and tells him to fight Captain America, and Peter reluctantly gets in a wrestling match with Cap, saying that he has to or his Aunt May will die. But then Cap tells him that they have Aunt May in protective custody, and when Peter believes him, he starts attacking Osborn, his head back in the game.
Meanwhile, Wasp easily defeats Octopus by flying into his mouth and incapacitating him from the inside. Kraven is taken out when a stray lightning bolt from either Thor or Electro strikes him. Iron Man loads the genetic sequence for Sandman into his armor, and shoots Marko, easily defeating him as he bursts into a shower of sand. Meanwhile, Captain America continues to fight with Green Goblin, until Harry Osborn shows up. Harry tries to plead with his father to stop.
As Harry pleads with his father, Iron Man loads the Goblin's genetic sequence into his armor. For a moment, Norman appears as though he has heard Harry's pleas and begun reverting back to his human form, but then Iron Man shoots him with the sequence, causing him to mutate even further. Suddenly, Fury appears behind Harry (having been cloaked there the whole time), and along with Cap, Hawkeye, and Iron Man, successfully incapacitate Goblin. Up in the air, Thor has defeated Electro. In the aftermath of the battle, Peter tries to console Harry, but Harry swears that he'll kill everyone for this.
The Six have all been taken into custody, and in the Triskelion, Janet visits the bed-ridden Hank. Peter reunited with Aunt May, and the two of them leave. In the story's final sequence, Captain America has another conversation with Fury, and notes that people 'will wars into existence'. Fury angrily blows him off and leaves.