Much like the Fantastic Four: House of M miniseries, Spider-Man: House of M is a standalone story that takes place in an alternate universe inspired by the House of M, however the events do not affect the story of the actual House of M series nor the characters of the restored mainstream Marvel Universe.
In the House of M universe, Spider-Man is famous for being an actor, super-hero, wrestler, and businessman. His identity as Peter Parker is known to the public, who believes he is a mutant born with his powers. Both his Uncle Ben and Gwen Stacy are alive; Peter and Gwen are married and have a son together. Rhino is Peter's bodyguard, even though he is not needed. J. Jonah Jameson, after years of publishing anti-Spider-Man articles, takes a high-paying job as Peter's publicist, where Peter constantly humiliates Jameson in public.
At Peter's surprise birthday party, Jameson is attacked by the Green Goblin, who states his intention to use Jameson to destroy Spider-Man. Jameson awakens the next morning holding Peter's journal, part of which explains how he got his powers and that he is not a mutant. Spider-Man searches all over the city to find Jameson, but it's too late. J. Jonah Jameson, with a camera crew, reveals the truth in Spider-Man's journal.
After the news breaks, a mutant boy is beaten half to death for wearing a Spider-Man shirt. Peter visits the boy at the hospital, where he meets a mutant security guard who expresses respect for Spider-Man. An announcement comes in that Rhino is causing havoc downtown. The guard turns to face Peter, but sees only an open window.
Spider-Man tries to stop Rhino from destroying downtown, but gets attacked by angry mutant pedestrians. Rhino escapes and meets the Green Goblin, who he tells to meet him behind Parker's house tonight. As soon as Green Goblin arrives, he sees that Ox, Vulture, and Electro are there as well, and they all attack the Green Goblin. During the fight, Gwen Stacy runs to see what's going on. Rhino grabs the Green Goblin and lets Gwen take his mask off, revealing Peter Parker.
It is revealed that Peter has been having recurring nightmares of horrifying events that Spider-Man faced in the true Marvel Universe, including the death of Gwen Stacy and of Uncle Ben. Thinking him insane, his family believes that subconsciously, Peter may have created his Green Goblin persona to force the truth of his non-mutant origins to come out.
In the end, Spider-Man fakes his own death, leaving a note for the House of M, threatening to come back if Magneto doesn't "lay off the humans." The Parker family is last seen somewhere out in the countryside, contentedly building their new home away from civilization. For this story to fit in with the larger story told in House of M, the Parker family would have had to return to New York at some point, as it was there that Wolverine and the rest of the memory-restored heroes introduced him to Layla Miller.