To determine the frequency of a sustained remission and to assess the long-term prognosis of relapse and retreatment, 66 patients with severe hepatitis B surface antigen-negative chronic active hepatitis and prolonged follow-up after initial corticosteroid withdrawal (mean, 10 +/- 0.4 yr) were evaluated. Selection of patients was made from among 206 cases of severe disease. Twenty-four patients (36%) sustained remission for at least 5 yr (mean, 11 +/- 0.6 yr) after initial therapy, and 42 (64%) relapsed and were retreated. Patients who sustained remission had shorter durations of illness before therapy (8 +/- 1 vs. 14 +/- 2 mo, p less than 0.05) and they had greater laboratory improvements during treatment. The frequencies of cirrhosis and death were not significantly greater in patients who relapsed. Of the 42 patients who relapsed, 9 (21%) ultimately entered a sustained remission after retreatment. Remission for at least 5 yr was possible in 33 of the 66 patients (50%). Major drug complications developed more commonly in those who relapsed and required retreatment (59% vs. 29%, p less than 0.05). We conclude that 50% of patients who enter remission during initial therapy may ultimately achieve a sustained remission, especially if their disease is of short duration and adequately suppressed during treatment. Relapse does not affect long-term prognosis, but retreatment is associated with more side effects.