Prion protein inhibits Bax activation and Bax-mediated cell death in primary cultures of human neurons and in MCF-7 cells. To determine whether prion protein can protect against Bax-mediated cell death in vivo, wild-type, null and prion over-expressing mice were subjected to Bax-dependent ethanol induced neuronal apoptotic cell death and the brains were immunostained for active caspase-3 as a downstream marker of Bax activation. Bax activation occurs in all ethanol-injected mice independent of their genotype. A higher level of cell death is present in ethanol-injected null mice than in wild-type and prion over-expressing mice. We conclude that prion protein protects some, but not all neurons, against Bax-mediated cell death in this experimental paradigm.