AIMS:: We aimed to test the hypothesis that susceptibility to chronic HBV, HDV or 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, χ=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%, χ=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.