A genetically determined resistance or susceptibility to chronic hepatitis C virus (HCV) infection may make an important contribution to the course of liver disease and may be linked to the human major histocompatibility complex (MHC). The aim of this study was to investigate the HLA class II genotype profile in chronic hepatitis C and to determine the HLA-hepatitis C association. The experimental population was composed of 49 unrelated chronic HCV patients (31 females, 18 males; mean age, 54.4 +/- 1.7 years; range, 34 to 73 years). The control population consisted of 43 ethnically matched healthy donors. HLA-DR and -DQ alleles were studied for patients and controls by a PCR-sequence-specific-primer low-resolution method. Anti-HCV was investigated with enzyme-linked immunosorbent assay II, and HCV RNA was investigated with reverse transcriptase nested PCR. The HLA class II allele, DRB1*11, was found at reduced frequency in 49 patients with chronic hepatitis C (anti-HCV and HCV RNA positive) compared to that for controls (22.4 versus 51.0%; P < 0.01, odds ratio = 0.3, confidence interval = 0.1 to 0.7). No further HLA associations with chronic HCV infection were observed, and there was no correlation between the stage of disease and HLA. DRB1*11 was also found at reduced frequency in all HCV antibody-positive patients compared to controls (corrected P = not significant). DRB1*11 was associated with chronic HCV infection, and it is possible that HLA-DRB1*11 may have a protective feature in chronic HCV infection. In addition, DRB1*11 was associated with protection from HCV infection. These findings suggest that host HLA class II genotype is an important factor determining the outcome of infection with HCV.