HIV establishes a chronic infection in the central nervous system (CNS) of AIDS patients. The immunopathogenesis of this chronic encephalitis is unknown. Because of the importance of major histocompatibility (MHO class I and class II antigens in modulating the immune response, we examined the tissue expression of MHC molecules in relation to CNS damage and expression of viral antigens. By immunocytochemical staining we found that β2-microglobulin (β2M) expression is elevated in all cases with signs of viral encephalitis. β2M was expressed at high levels on endothelial cells, macrophages and possible oligodendroglia within regions of histopathology. In histologically normal regions elevated expression of β2M was noted only on endothelial cells. MHC class II expression was elevated only in the HIV encephalitis cases, and was restricted to macrophages/microglia and occasional endothelial cells. When compared with other viral encephalitides these findings suggest that the intra-CNS immune response to HIV is appropriate for viral presentation; however, the absence of responsive systemic T cells may lead to chronic viral infection.