Prions are notoriously resistant to inactivation. To prevent accidental transmission of variant Creutzfeldt-Jakob disease (vCJD), various decontamination procedures have been adopted for re-usable medical devices by the authorities of countries at risk. As the vCJD agent in humans has a wide tissue distribution, practical methods of prion decontamination urgently need to be standardized, as do other sterilization and disinfection procedures (European Committee for Standardization). This article proposes a method using a quantitative murine model, combining observations of the decrease in the infection rate, the increase in the incubation period and a simultaneously performed chemical protein fixation control. In terms of practical application, autoclaving at 134°C for 18min or 121°C for 30min, and 1N sodium hydroxide for 15min reduced the transmission of infectivity by a factor of at least 10⁶. Partial efficacy can also be identified by the methodology, particularly for liquid cold sterilants such as glutaraldehyde and peracetic acid solutions.