To assess the efficacy of oral pulse prednisone therapy after relapse of severe autoimmune chronic active hepatitis and to determine the effects of such therapy on serum immunoglobulin G levels and peripheral blood lymphocyte subsets, 16 patients were randomized after relapse to therapy with prednisone 90 mg daily for 5 days each month or conventional daily dose therapy with prednisone in combination with azathioprine. Seven of the eight patients randomized to pulse therapy failed treatment after 1.9 +/- 0.7 months (range, 24 days to 6 months). Treatment failure occurred more commonly (87 vs. 0%, p < 0.01) and remission occurred less frequently (0 vs. 87%, p < 0.01) in patients receiving pulse therapy. The percentage and absolute numbers of circulating CD2 and CD4 cells decreased during relapse, while CD8 and CD20 cell counts were not significantly altered. Pulse therapy was associated with a significant increase in the percentage of CD4 cells and decrease in aminotransferase levels after 5 days. Serum immunoglobulin G levels, however, were not affected by treatment and after 1 month the biochemical findings and lymphocyte subsets were again similar to those at relapse. In contrast, serum immunoglobulin G levels decreased after 14 days of combination therapy and by 1 month the numbers in all lymphocyte subsets were higher than at relapse. We conclude that oral pulse prednisone therapy is ineffective for patients in relapse. The numbers of circulating CD2 and CD4 cells fall during relapse and increase as inflammatory activity subsides during corticosteroid therapy. Combination therapy reverses the biochemical changes and alterations in peripheral blood lymphocyte subsets that accompany relapse.