Lymphocytes from 39 patients with HBsAg positive chronic liver disease were incubated with their own hepatocytes to investigate mechanisms of lymphocyte-mediated liver damage. Cytotoxicity was significantly increased in 46% overall, and in 73% of those with chronic active hepatitis. Unlike HBsAg negative chronic active hepatitis where only non-T cells were cytotoxic, HBsAg positive patients had both cytotoxic T and non-T cells. A purified liver membrane complex (LSP) and aggregated IgG both blocked non-T cytotoxicity without affecting T cell cytotoxicity; this suggests that the former is probably an antibody-dependent cell-mediated reaction against normal membrane components. This was confirmed in preliminary studies which demonstrated that preincubation of hepatocytes with the F(ab)2' fragment of an anti-human IgG reduced non-T lymphocyte cytotoxicity. T-cell cytotoxicity was restricted to HBeAg-positive patients, suggesting a relationship between T-cell cytotoxicity and viral replication. Purified HBsAg, however, blocked cytotoxicity in only three of 11 cases. Non-T lymphocytes reacting with normal membrane components may contribute to liver damage in both 'autoimmune' and virus-associated chronic liver disease, whereas cytotoxic T-cells, probably reacting with viral determinants, are exclusive to those with viral replication.