To evaluate the efficacy of low-dose corticosteroid therapy after multiple relapses of severe HBsAg negative chronic active hepatitis, 22 patients who had relapsed on 3.4 ± 0.4 occasions (range = two to seven relapses) were treated with the lowest dose of medication necessary to ameliorate symptoms and maintain serum AST activity below five-fold normal. Results were compared with those in 31 patients who had received conventional retreatments after 3.4 ± 0.3 relapses (range = two to eight relapses). During 44 ± 7 mo of low-dose therapy (range = 9 to 149 mo), one patient (5%) entered sustained remission, 16 patients (72%) continued treatment, two patients (9%) died of liverrelated complications and one patient (5%) died of a nonliver-related cause. Drug-related side effects improved in 11 of 13 patients who had acquired them during conventional therapy (85%). The median dose of prednisone was 7.5 mg daily (range = 1 to 17.5 mg) with and without azathioprine. Thirteen patients received long-term treatment consisting of 10 mg or less of prednisone only. Patients receiving conventional treatment entered remission more frequently than those on low-dose therapy (97% vs. 36%, p < 0.001) but they relapsed after drug withdrawal (53% vs. 87%, p > 0.1), required continuous therapy (55% vs. 72%, p > 0.1) and died of liver-related complications (10% vs. 9%) as commonly as those receiving low-dose therapy. We conclude that low-dose corticosteroid therapy in patients who have experienced multiple relapses has similar efficacy and less morbidity than conventional retreatments.(HEPATOLOGY 1990;11:1044-1049.).