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 < 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 < 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.