In the eponymous episode "Medicinal Fried Chicken", the location first appears when medical marijuana becomes legal and all of the Kentucky Fried Chickens in Colorado are replaced with Medicinal Fried Chicken. After the men of South Park (led by Randy Marsh) purposely give themselves testicular cancer in order to get medical marijuana, the state reaches the conclusion that due to the sudden rise after KFC closed, Kentucky Fried Chicken must be a deterrent for testicular cancer. Thus, the KFC is reopened.
The store makes another appearance in South Park: The Fractured But Whole. It is a location related to the game's main story, where The New Kid goes to pick up a medication for Classi as part of a qest. There, they encounter Towelie and must make him stoned. It is shown to have a complex security system that can't be bypassed until the player unlocks TimeFart Pause and uses it to turn off the alarm.
- Medicinal Fried Chicken is based off of Kind for Cures in Los Angeles. Now closed, Kind for Cures had purchased a building previously occupied by a Kentucky Fried Chicken restaurant and purposefully named their store after the initials of KFC.