To determine whether an autoimmune reaction to liver-specific proteins occurs in alcoholic liver disease, the cytotoxic effect of lymphocytes on isolated hepatocytes was determined in 27 alcoholic patients. Cytotoxicity was demonstrated in 15 of 17 patients with a histological diagnosis of alcoholic hepatitis, but in none of 10 with other forms of alcoholic liver disease. The ability of a liver-specific membrane lipoprotein to block the reaction suggests that sensitization to this antigen is responsible for the cytotoxicity. The demonstration of cytotoxicity using T cell-depleted, but not B and K cell-depleted, lymphocytes suggests an antibody-dependent cell-mediated reaction. There was a close correlation between cytotoxicity and the presence of alcoholic hyalin, liver cell necrosis, and piecemeal necrosis, but not with other histological features, immunoglobulines, autoantibodies, or standard liver function tests. The persistence of this autoimmune response, induced in some way by alcohol or one of its metabolites, may be important in the progression of acute alcoholic hepatitis to chronic liver disease.