Human leukocyte antigens (HLAs) of class I and class II are reported to influence the outcome of hepatitis C virus (HCV) infection. The aim of this study was to assess the role of HLA class I and class II in influencing spontaneous viral clearance or persistence in HCV-infected patients. HLA class I (A and B) typing was performed by lymphocytotoxicity test and HLA class II (DRB1) was determined by low-resolution PCR-SSP (polymerase chain reaction amplification with sequence-specific primers) for 99 subjects (48 men and 51 women). Of these, 75 had chronic infection and 24 had viral clearance. No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, source of infection, and risk factors. HLAB-w35 and HLA-DRB1*08 occurred more frequently in those with viral clearance (21.7 and 16.6%, respectively) compared with those with chronic infection (5.5 and 2.6%; p < 0.04 and p < 0.01, respectively). DRB1*15 occurred more often in those with chronic infection (29.3%) compared with those with viral clearance (16.66%), but the difference did not reach statistical significance. These results support the hypothesis that specific HLA class I and class II alleles might influence the clearance or persistence of HCV infection. Both Bw35 and DRB1*08 are associated with clearance of circulating HCV whereas DRB1*15 appears to predispose to progression of liver disease in Tunisian patients. Taken together, our results and those previously reported suggest that HLA associations with the outcome of hepatitis C viremia vary in relation to the ethnicity of the population studied. Further prospective studies of larger cohorts of HCV-infected subjects are needed to evaluate, in different populations, the role of specific HLA class I and class II alleles in the outcome of HCV infection.