Hepatitis C virus (HCV) leads to chronic liver disease in at least 50-60% of infected people and approximately 40-50% of these patients will go on to develop cirrhosis due to chronic hepatitis C (HCV-C). The pathogenic mechanisms that result in HCV-C are unknown. Sixty Japanese patients with HCV-C were examined for HLA-A, B, C and DR alleles by serologic typing and for HLA-DQB1 alleles by DNA typing using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. As the control population, 293 healthy un-related Japanese were used. The frequencies of HLA-B61, C(omega)3, DR4, DQB1*0401 and DQB1*0402 were increased, while those of HLA-DR9, DQB1*0301 and DQB1*0303 were decreased in the patients. The co-ordinate increase in the frequency of HLA-DR4, DQB1*0401 or 0402 and decrease in the frequency of DR9 or DQB1*0303 were suggestive of a strong linkage disequilibrium between HLA-DR4 and DQB1*0401 or 0402 and between HLA-DR9 and DQB1*0303, respectively. From the odds ratio (OR) analysis, the combinations of HLA-C(omega)3+ DR4-DQB1*0401 or 0402, or HLA-B61 + DR4 - DQB1*0401 or 0402 increased the risk for developing HCV-C when compared to each HLA allele alone. This suggested an additive effect for these classes I and II HLA allele combinations in HCV-C. In contrast, HLA-DR9-DQB1*0303 and DQB1*0301 may confer resistance to this disease. These results suggest the existence of HLA-linked susceptibility genes to HCV-C.