A boy, Dan, comes over to a girl's house and has to clean thoroughly before the mother, Barbara, will let him see her daughter Melinda. Dan has to don a mask and it becomes clear Melinda is all but a prisoner in her own home. Melinda insists Dan remove her mask and he reluctantly agrees – they kiss. Then he notices Melinda's skin is blistering and she goes into respiratory distress. He fumbles an injection which her mother manages to administer.
House gets up in the morning before Wilson and sets out dirty dishes to wash. Wilson lets him know Cuddy has called about Melinda going into anaphylactic shock. Wilson thinks House is trying to get him out after his apartment deal fell through. Wilson reveals the reaction occurred when Melinda was in a clean room.
House and staff determine Melinda had a heart transplant and has been in a sterile environment for six months. Foreman believes that's too long, and House figures someone's lying. Melinda insists Foreman should let her be released and Barbara admits she's too protective but with good reason. Cameron and Chase go over the house and figure Dan snuck in via the window and had sex a few nights earlier. They get a sperm sample from Dan and the test show it's not responsible, but House is skeptical. He confronts Dan who reveals he took penicillin for a week, and House points out she was allergic to it but it's out of his system by the time they tested.
After House decides not to tell the parents, Cameron assures them it won't happen again but then Melinda goes into a seizure and Cameron determines it's her heart. They try and determine if it actually is congestive heart failure but the tests prove clean. Melinda is worried she'll lose her transplanted heart.
Wilson arrives home to find that House has left a stethoscope on the door, indicating he's "not to be disturbed." House finally lets him in hours later only to find no one was in…except House. They discuss the case but Wilson ends up frustrated at his home life. Foreman and the parents go to visit Melinda only to find that she's gone. They conclude she's gone outside and Foreman heads for the roof and finds her halfway up the stairs. He talks with Melinda who reveals her mother has always been over-protective. She agrees to go downstairs but Foreman notices her left foot is dragging and she admits it feels "weird." Foreman notices a muscle twitch that's an indicator of paralysis…starting with the legs.
A DDX proves useless and they run more tests while filtering her blood for the blood cells they believe are causing the problems. House returns home where Wilson confronts him about the missing voice mails and House admits he erased the messages to keep Wilson there. House points out Wilson might as well stick around until he admits to himself his marriage is over, and all they can do is laugh.
Melinda is getting progressively worse and refuses to see Dan. Foreman suspects mood swings due to the medication but her mother asserts Melinda has given up. Melinda has another attack and they intubate – the paralysis has reached her lungs. House concludes she has botulism from food that Dan brought in and they start another test while House goes to confront Melinda. Melinda's parents take the staff off the case and put Cuddy in charge, and House goes in. Wilson is providing a consult and House interrupts to remove the tube and demands an answer from Melinda. She reveals he was on a non-penicillin antibiotic and Don went through tall grass, picking up ticks that are giving her paralysis. House searches for ticks while Melinda has another attack and Cuddy pulls House off. House appeals to the parents and Wilson recommends a radical drug and they move her to the ICU.
En route to the ICU, Foreman takes Melinda into the elevator where House is waiting. House shuts down the elevator and starts looking for the ticks again. When Foreman goes for him, they struggle and she has another seizure – House convinces Foreman they need to treat the cause, not the symptoms. Working together, they revive her then look for the ticks. They've looked over every inch of skin and Foreman starts the elevator, but then House realizes where the tick is – in her vagina. Melinda will recover while House confronts Wilson on how he moved Melinda to ICU to secretly support House.
Melinda is ready to leave and Barbara cuts the cord and lets her go to school and see her friends. House arrives home and he and Wilson share the couch and watch TV. Wilson admits he's finally called a divorce lawyer.