Expression of major histocompatibility complex (MHC) molecules on cells of the central nervous system (CNS) plays an important role in the pathogenesis of acute viral encephalitis. We have compared the induction of MHC class I and II mRNA transcripts in mice upon infection with the virulent challenge virus standard (CVS) strain of rabies virus and avirulent rabies virus variant RV194-2. Rabies virus antigen was detected with immunoperoxidase staining and 35S-labeled RNA probes were used to detect MHC class I and class II mRNA transcripts by in situ hybridization in infected brains. In CVS and RV194-2 infected animals, MHC class I mRNA expression occurred in the brain in neurons, glia, choroid plexus epithelial cells, ependymal cells, and inflammatory cells; expression was moderately higher in CVS-infected mice. In contrast, MHC class II mRNA expression was minimal in CVS-infected mice and it was markedly upregulated in CNS inflammatory cells upon RV194-2 infection. Both viruses induced an acute inflammatory reaction in the cerebrospinal fluid (CSF), which was more pronounced in CVS-infected mice. Both viruses also induced an antigen specific T and B cell response detectable in lymph nodes and spleen. These studies, which show a correlation between greater expression of MHC class II mRNA in the brain following intracerebral RV194-2 infection and protection against RV194-2 infection in the brain, suggest that recovery from avirulent rabies virus infection of neural cells involves T helper cells produced and/or retained in the brain for reasons that are not entirely clear.