Previous studies demonstrated that peripheral blood lymphocytes are cytotoxic to autologous hepatocytes in patients with chronic hepatitis B virus infection. We examined whether cytotoxicity is specifically directed against hepatocytes expressing HBsAg or HBcAg. Viral antigens were detected by immunofluorescence in isolated hepatocytes before and after exposure to T and non-T lymphocytes from 28 patients with chronic HBV infection in an autologous cytotoxicity assay. There was significant reduction in the percentage of HBcAg-positive hepatocytes after exposure to T lymphocytes and, to a lesser extent, after exposure to non-T cells; hepatocytes expressing HBsAg were not affected. Other studies showed that many hepatocytes containing HBcAg have IgG of anti-HBc specificity bound to their nuclei. In the present study, there was significant association between the presence of HBcAg and nuclear IgG in isolated hepatocytes. The ratio between the percentages of HBcAg-positive and IgG-positive hepatocytes (reflecting the proportion of hepatocytes containing free-core antigen) correlated significantly with reduction in HBcAg-positive liver cells after exposure to T cells, but not to non-T cells. These results suggest that hepatocytes in which viral replication is occurring and which express core determinants are susceptible to cell-mediated cytotoxicity and that T-cell cytolysis may be modulated by anti-HBc which is bound to hepatocytes.