To assess the clinical and prognostic implications of human leukocyte antigen B8 in corticosteroid-treated severe autoimmune chronic active hepatitis, 81 consecutive patients were tested for histocompatibility antigens on the A and B loci, treated with corticosteroids, and followed prospectively for 111 +/- 8 mo. The 47 patients with HLA-B8 were younger (38 +/- 2 yr vs. 48 +/- 2 yr; p less than 0.01), had higher serum levels of aspartate aminotransferase (658 +/- 60 U/L vs. 465 +/- 49 U/L; p = 0.02) and bilirubin (7 +/- 1 mg/dl vs. 2.8 +/- 0.4 mg/dl; p = 0.003), and more commonly had histologic features of bridging necrosis, multilobular necrosis, and cirrhosis (85% vs. 56%; p less than 0.01) at presentation than the 34 patients without HLA-B8. Remission (79% vs. 71%), relapse after drug withdrawal (76% vs. 71%), treatment failure (13% vs. 6%), progression to cirrhosis (46% vs. 32%), and death from liver failure (6% vs. 3%) occurred as frequently in patients with and without HLA-B8. Importantly, HLA-B8-negative patients with HLA-A1 relapsed less frequently than HLA-B8-positive patients with and without HLA-A1- and HLA-B8-negative counterparts without HLA-A1. It is concluded that HLA-B8-positive patients are younger and have more severe disease at presentation than HLA-B8-negative patients. The HLA-B8 phenotype does not influence the response to corticosteroid therapy. HLA-B8-negative patients with HLA-A1 relapse less frequently than other phenotypes.