To determine if autoimmune features influence the prognosis of severe sporadic chronic active hepatitis of uncertain etiology, 126 corticosteroid-treated patients who had been screened to exclude active hepatitis B infection and possible drug effects or transfusion-related disease were categorized according to the presence of the lupus erythematosus cell, antinuclear antibody, smooth muscle antibody, and coexistent autoimmune diseases. Patients with autoimmune markers had findings similar to those without these features and responses to therapy were comparable. Remission (77% vs. 68%), treatment failure (16% vs. 14%), progression to cirrhosis (31% vs. 39%), and death from hepatic failure (4% vs. 12%) occurred with similar frequency in patients with and without the lupus erythematosus cell or antinuclear antibody. Although patients with the lupus erythematosus cell or antinuclear antibody tended to relapse less frequently than others, 5-yr survival was not increased (92% vs. 87%). Autoimmune diseases occurred as commonly in patients without the lupus erythematosus cell or antinuclear antibody as in those with these findings (16% vs. 17%), and the presence of these conditions did not identify patients with a different clinical behavior. In severe sporadic chronic active hepatitis of uncertain etiology, a clinically and prognostically distinct subgroup reflective of a possible autoimmune disorder cannot be defined.