An in vitro cytotoxicity system was developed for studying patients with chronic active liver disease using as the target cells 51Cr-labeled avian erythrocytes coated with cell membrane lipoprotein extracted from human liver and, as the aggressors, mononuclear cells from peripheral venous blood. Approximately 50% of 62 patients with chronic active liver disease showed cytotoxicity in this test system as did 5% of 100 apparently healthy controls. In addition, mild cytotoxicity was shown by 2 of 8 patients with the primary biliary cirrhotic syndrome and 2 of 17 persons with other liver diseases. No specific antibody was added to the test system and the cytotoxicity could be inhibited by free lipoprotein, antilipoprotein, and by aggregated Ig. Cytotoxicity also was abolished by the depletion from the mononuclear cells of cells phagocytic for iron filings. The effect of depletion of these phagocytic cells was not restored by the addition of 2-mercaptoethanol. These findings add further evidence that autoimmune responses to liver tissue occur in many patients with chronic active liver disease and, importantly, suggest also that these may occur in some apparently healthy people.