Prion diseases are fatal, infectious, neurodegenerative disorders with special implications for infection control in the OR.The causative agent is highly resistant to disinfection and sterilization processes and has been transmitted during health care interactions. It is important to use evidence gained through research and case reports to minimize risk of infection. This article describes an infection control protocol developed for identifying high-risk patients, providing perioperative care, decontaminating the OR, and protecting health care personnel. This protocol provides multidisciplinary team members with a guideline for preventing transmission of these fatal diseases. AORN J 69 (May 1999) 946-967.