Antibodies to ANA and other autoantibodies may occur in chronic hepatitis C, it is possible that host factors such as human leucocyte antigen (HLA) differences are important. Our aims to investigate the frequency of seroiogical markers of autoimmunity in chronic hepatitis C, and to correlate them with serum alanine aminotransferase (ALT) levels, and HLA-DR phenotypes. We designed two studies on 49 patients with chronic hepatitis C infection. The first one was an epidemiological survey aimed to determined the prevalence of chronic hepatitis C-associated autoantibodies. In the second study, the distribution of different HLA Class II genes was examined by DNA analysis in patients with chronic hepatitis C (n=49), chronic hepatitis C patients with autoimmunity (n=26), and chronic hepatitis C patients without autoimmunity (n=23). Serum specimens of these patients were tested for rheumatoid factor (RF), immunoglobulin patterns, and autoantibodies including antinuclear (ANA), anti-smooth muscle (ASMA), antimitochondrial, antithyroid microsomal (ATM), antithyroglobulin (ATG) and anti-LKM1 autoantibodies. RF (>10 IU/ml) was more frequently observed in groups I (49.0%), group II (53.8.0%), and group III (43.5%) than in control, although the difference was not statistically significant (p > 0.6). There was a statistically significant difference between the prevalence of at least one autoantibody in chronic HCV patients (57.4%). and healthy control (23.5%, p< 0.001). The occurrence of at least one autoantibody and/or the presence of RF > 10 IU/ml did not correlate with either serum ALT levels. HCV- associated autoantibodies were associated with human leucocyte antigen DRB1*04. DRB1* 04 antigen of Class II was statistically significant increase (p< 0.05, OR= 4.75, with a 95% [CI] of 1.1 to 23.8). On the basis of these results it is possible that HLA-DRB1*04 may be susceptibility markers for HCV-associated autoimmunity. © 2001 Blackwell Science Ltd,.