To assess the frequency and significance of immunoglobulin G antibody to double-stranded DNA in chronic active hepatitis, 99 patients with severe disease were tested for the antibody by an enzyme-linked immunosorbent assay of established sensitivity and specificity. Antibody was detected in 56 patients (57%) and occurred with similar frequency in patients with autoimmune (64%), idiopathic (46%) and type B (43%) disease. The mean serum level of antibody was higher in autoimmune disease but it was not significantly different from that in the other diagnostic categories. Patients with and without the antibody could not be distinguished by clinical, laboratory or histologic findings. Responses to corticosteroid therapy and mortality were unrelated to antibody status. In five patients, the antibody disappeared after corticosteroid treatment and induction of histologic remission. We conclude that immunoglobulin G antibody to double-stranded DNA is frequently present in patients with severe chronic active hepatitis. Patients with autoimmune disease may have higher antibody levels than others, but the presence of antibody does not connote a disease of specific etiology, unique presentation or different behavior. The prevalence of the finding and its disappearance after corticosteroid therapy suggest that it is a nonspecific manifestation of inflammatory activity.