Immune mechanisms have been implicated in chronic viral hepatitis, and these may be influenced by genetic factors. To determine if disease severity in chronic viral hepatitis is associated with the human leukocyte antigens DR3 and/or DR4, 109 patients were evaluated prospectively. The frequencies of DR3 and DR4 in these patients were compared to those in 80 normal subjects. Patients with DR3 and/or DR4 had the same occurrence of severe disease as patients with other DR antigens (21% versus 30%, P = 0.3). Patients with DR3, however, had higher serum gamma globulin and immunoglobulin G levels than patients with DR4 and a greater frequency of severe disease (36% vs 12%, P = 0.046). Patients with DR4 had concurrent immunologic diseases more commonly than patients with DR3 (44% vs 9%, P = 0.005) and patients with other DR antigens (44% vs 9%, P = 0.0002). Patients with DR4 but not DR3 had severe disease less frequently than other patients (9% vs 31%, P = 0.02). The frequencies of DR3 in patients with severe disease (37% vs 18%, P = 0.06) and DR4 in patients without severe disease (44% vs 30%, P = 0.07) were different than those in normal subjects but not to a statistically significant level. We conclude that patients with DR3 and DR4 have different clinical and laboratory findings and disease severity. Patients with DR4 have milder disease than patients with other DR antigens. Disease severity, however, is not closely associated with DR3 or DR4.