Cellular prion protein (PrP(C)), a cell-surface glycoprotein normally associated with neurons, is also expressed in other cell types such as glia and lymphocytes. To further elucidate these roles of PrP(C), wild-type prion protein gene (Prnp(+/+)) mice and Prnp-deficient (Prnp(-/-)) mice were infected with encephalomyocarditis virus B variant (EMCV-B) via an intracranial route. EMCV-B causes encephalitis and apoptotic cell death in vivo. Histopathological studies revealed that Prnp(+/+) mice infected with 600 pfu of EMCV-B showed more severe infiltration of inflammatory cells, accompanied by higher activation of microglia cells around the hippocampus, than Prnp(-/-) mice; viz., no differences in the brain virus titer between these two lines of mice. Terminal deoxynucleotidyl transferase (TdT)-mediated dUTP, nick end-labeling (TUNEL) staining of the brain specimens revealed that the CA1 hippocampal pyramidal cells showed a larger number of apoptotic neurons in Prnp(-/-) than Prnp(+/+) mice. Based on all these findings, PrP(C) may play certain roles in the induction of inflammation and inhibition of apoptosis in vivo.