Prion diseases constitute a unique infection control problem because prions exhibit unusual resistance to conventional chemical and physical decontamination methods. Recommendations to prevent cross-transmission of infection from medical devices contaminated by Creutzfeldt-Jakob disease (CJD) have been based primarily on prion inactivation studies. The recommendations in this article consider inactivation data but also use epidemiological studies of prion transmission, infectivity of human tissues, and efficacy of removing microbes by cleaning. On the basis of the scientific data, only critical (e.g., surgical instruments) and semicritical devices contaminated with high-risk tissue (i.e., brain, spinal cord, and eye tissue) from high-risk patients--those with known or suspected infection with CJD--require special treatment.