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The episode's opening, conceived by film director Guillermo del Toro, is a mash-up of horror movies, science fiction films and TV shows, including all of del Toro's own films, ending with Lisa falling through the couch, dressed as Alice from Alice in Wonderland, and getting brainwashed by The Hypnotoad from Futurama, then happening upon a palace room in a send-up of the end of Pan's Labyrinth.
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It is Halloween night in a Dr. Seussian take on Springfield. The Simpson children are home with the mumps and unable to go trick-or-treating. Once their mother Marge (in a Catwoman costume that every other woman and The Comic Book Guy is wearing) leaves for a costume party, they are visited by The Fat in the Hat (Homer) who gives them vaccinations so he can take them out to get candy for them and beer for him. However, instead of helping the children get their treats, he takes them on a path of death and destruction; blowing up Mr. Burns' mansion and feeding him to a homeless shelter, robbing Moe and skinning him, robbing Apu and forcing him to spend time with his wife and children, killing two DMV workers (Patty and Selma) and tossing car licenses to people waiting in line, blowing up town hall while wearing a Guy Fawkes mask, and committing "aggravated Flu-Fluffel-cide."
The children are alarmed at those events and manage to elude him with the aid of several animals; a Barney Gumble-esque camel, a Krusty-esque bull, and on the wings of the Mexican Bumblebee Man. However, Fat is waiting for them when they get home and gloats that he will never leave them right before baby Maggie stabs Fat in the chest with his own umbrella. Marge comes home, unaware of what happened, and the children fake their mumps by stuffing the collected candy in their mouths and have turned the Fat in the Hat into a rug.
After getting decapitated during a day of flying his box kite in a fly zone near the Springfield airport, Bart is surgically attached to Lisa's body in order to extend Bart's life and cut Lisa's short. Though the two eventually get along, Bart learns that he can control Lisa's body while she is unconscious and resolves to get rid of her to have total control. Unfortunately, the attempt on the sawmill results with Bart transferred to Selma's body (who needs a karaoke partner) while Lisa is grafted onto Krusty (who needs a comedy partner for an upcoming act).
In a 1930s' circus, the self-serving strongman Homer gets his lover trapeze artist Marge to marry sideshow freak Moe after learning of the emerald ring he inherited from his mother on her death bed. At their wedding reception, the other "freaks" announce that they accept Marge in spite of her being a "normal" outsider (even though Marge claims she is a freak because she has one blue eye and one pale brown eye). After finding Homer attempting to poison Moe's wedding wine glass, Marge kicks him out of her trailer. Homer is then cornered by the freaks with weapons as they advance on him with the intention to mutilate him into a freak like them. The scene then cuts to the present, where it is revealed that the whole story was told by a "Duck Man" Homer of how he met Marge.