Aims: We aimed to test the hypothesis that susceptibility to chronic HBV, HDV and HCV infections or their pathology is influenced by host genetic factors., Methods: The Human Leukocyte Antigens (HLA) (A, B, DR and DQ) were determined by microlymphocytotoxicity assay in patients with chronic C (n = 117), B (n = 97) or D (n = 27) hepatitis and their frequencies were compared with those of 489 healthy controls., Results: No statistically significant association was found between any HLA antigen and chronic B or D hepatitis. A significantly higher frequency of HLA-B14 was observed in patients with chronic persistent or active C hepatitis (16.7% of 90 versus 5.9% of 489, chi(2) = 10.9, pc < 0.05, Relative Risk = 3.17, Etiological Fraction = 0.11). The frequency of HLA-DR5 was lower in HCV positive patients (24.8%) than in controls (45%, chi(2) = 15.1, pc < 0.005, RR = 0.4, EF = -0.37)., Conclusions: No correlation could be observed between clearance of HBV or HDV and HLA phenotype. Immunogenetic factors may have a role in determining susceptibility to chronic HCV hepatitis, and in Italian patients HLA-DR5 is a protective factor.