Dr. Connors studies how reptiles can regenerate a lost limb and decides to develop a serum that will duplicate this ability in humans. Connors creates a serum that successfully regenerates a leg on a rabbit within an hour and immediately tests it on himself. Connors downs the serum and feels a stange sensation in his right shoulder, then instantly, he grows a new arm, but the new arm suddenly turns green and scaly and the rest of Connors turns green and scaly. Sobbing and trembling like a man possessed, Connors leaves his lab and runs out into the night. Three guys are hanging out on the street when a human-sized lizard confronts them. The three guys run for their lives. After this encounter, stories of some kind of monster in the city's sewers start to spread and are soon proven when "Lizard" attacks subway workers. The workers are saved by Spider-Man, and he and Lizard have their first fight, during which, Peter discovers Lizard is Connors, and afterwards, asks for access to Connors' notes.
One week later, J. Jonah Jameson rushes out of his office at the Daily Bugle and orders Betty Brant to grab her book and call Parker to meet them with his camera. The word is out that Kraven The Hunter is arriving at the pier from Africa, and JJJ thinks this will be the biggest story of the year. At the pier, Peter shows up, and Jonah barks at him to get his camera ready. Kraven comes off the boat and walks by. JJ calls for Kraven to wait and offers money for an interview, but Kraven states that he’s not interested in giving interviews; he’s there to hunt the most dangerous game of all. JJ approaches Kraven with a question: since there are no wild beasts in New York, what is Kraven planning to hunt? Kraven replies that the most dangerous game in New York is Lizard and goes his own way. Peter tries to stop Kraven, but it's no good, so Peter is forced to do so as Spider-Man, and when Kraven meets Lizard for the first time, Spider-Man is there. The three get into a fight with Spider-Man trying to save Lizard.
One night, Peter awakes from a nightmare and goes for a swing. Spider-Man is swinging, and Kraven drops down onto a rooftop. Spider-Man is hit by a dart and raises his head to see Kraven. Knowing he's being drugged, he attacks Kraven, only to be caught in a net. Kraven takes Spider-Man to a cemetery and lowers his body into an empty grave. Kraven throws in the dirt and covers the hole.
In the sewers, Lizard finds a newspaper and sees a photo of Spider-Man, when Kraven drops in. They duke it out. Kraven wins and leaves the sewers carrying Lizard. Meanwhile, a hand bursts out of Spider-Man's grave. Thinking of how much he loves Mary Jane, he comes out of the grave and leaves the cemetery, then heads off to the lab, where he examines Connors' notes and whips up a compound in a tube, creating an antidote that will restore Connors to normal, before swinging off into the night.
While he swings, he finds Kraven and follows him. Spider-Man looks to see Lizard inside a cage and goes for Kraven. He grabs him and throws him to the floor. Kraven gets up, then Spider-Man loses control and starts beating Kraven. He holds himself when his foe seems defeated and gives Lizard the cure, but Kraven recovers and attempts to kill Spider-Man, only to accidentally kill himself. The antidote kicks in, and Lizard turns into one-armed Dr. Connors again. Spider-Man frees him from the cage and takes Connors home. Connors decides he has tampered with nature and burns his notes on the spot. He prepares to face the penalty for his crimes, but Spider-Man suggests that the whole thing be kept a secret between the two of them.
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