After Ed Snow discovers his wife Elyse constantly sleeping for several days, she is admitted to the hospital. Dr. Cameron is very interested in the case. So much so that her interest convinces House to take the case. The doctors are puzzled by her symptoms, considering everything from tumors to breast cancer to rabbit fever. When all the treatments fail, House concludes she has African sleeping sickness contracted through sexual intercourse. However, neither Elyse nor Ed has ever been to Africa. Neither one will admit to having an affair. She will die without the proper treatment.

Legendary jazz musician John Henry Giles checks into Princeton Plainsboro Teaching Hospital believing he's dying from ALS and signs a DNR to avoid a slow death. House disagrees with the diagnosis and goes against everyone's wishes when he violates the DNR to save Giles' life. The decision lands House in court, drives Foreman to consider taking another job, and results in Giles' paralysis worsening. But when the patient inexplicably starts getting better, the team has to figure out the mystery in reverse and find out why his condition is improving.