6x21 - The Grim Adventures of Billy and Mandy

When Billy finds his "son" Jeff the Spider lying in his bed with "Spider Pox", he goes to Mandy for help to get rid of the giant spider. While ignoring Billy, the next morning Mandy awakens afflicted by Spider Pox too, developing four additional arms and the ability to produce spider web. Mandy's condition progresses and she completely turns into a giant spider, who captures Billy's parents and Grim. Grim tells Billy that, to cure Mandy, he must use the venom of the spider that infected her. While Billy successfully gives Mandy Jeff's venom, he also carried the virus and infected the people of the city, who have all turned into spiders.