A method is described for determining the cytotoxicity of normal and autologous lymphocytes for 51Cr-labeled isolated parenchymal liver cells in a low aggressor to target cell ratio. Results were compared from patients with chronic active liver disease (CALD), chronic persistent hepatitis (CPH), miscellaneous liver diseases, or primary biliary cirrhosis (PBC). In 53% of CALD patients, lymphocytes showed greater cytotoxicity for hepatic cells than did normal allogenic lymphocytes, but in 32% there was significantly less 51Cr release than normal; in the remainder, results were in the normal range. Lymphocyte cytotoxicity was greater in patients with disease of short duration and less in those treated with corticosteroids. In untreated CALD, decreased 51Cr release was associated with the presence of plasma factor(s) inhibiting phytohemagglutinin (PHA)-induced transformation of normal lymphocytes. Lymphocytes from approximately 50% of the patients with PBC exhibited cytotoxicity for hepatic cells but 25% showed less 51Cr release than controls and the remaining patients had results in the normal range. Lymphocyte cytotoxicity was also greater during the earlier stage of PBC. In contrast to CALD, decreased 51Cr release was not associated with the presence of plasma factor(s) inhibiting PHA-induced transformation of normal lymphocytes. Our findings support the hypothesis of in vivo lymphocyte-mediated liver cell damage in CALD and PBC, suggesting a potentially important role for lymphocyte suppression in the pathogenesis of both diseases.