The transmissible agent that causes spongiform encephalopathies such as scrapie, the prion, is believed to be devoid of nucleic acid and identical with PrP(Sc), a modified form of PrP(C). PrP(C) is a normal host protein encoded by a single copy gene (Prn-p) and is found predominantly on the surface of neurons. PrP(Sc), in contrast to PrP(C), is resistant to protease and accumulates intracellularly. Prusiner proposed that PrP(Sc), when introduced into a normal host, causes the conversion of PrP(C) or its precursor into PrP(Sc) ('protein only' hypothesis). If indeed PrP is an essential component of the prion, then an animal devoid of the PrP protein should be resistant to scrapie. We generated homozygous PrP 'knockout' mice. These Prn-p(o/o) mice showed no gross abnormalities, and microscopic examination of brain sections of normal and Prn-p(o/o) mice revealed no differences. Prn-p(o/o), Prn-p+/+ and Prn-p(o/+) mice were inoculated with scrapie agent; the clinical response as well as the prion titer at different time points are being determined.