The influence of an immunosuppressive cytokine, interleukin-10 (IL-10), on the outcome of hepatitis C virus (HCV) infection has been increasingly reported recently. A number of polymorphisms appear to control the level of IL-10 production. Among them, −592C/A, −819C/T and −1082G/A in the IL-10 gene are three most studied single nucleotide polymorphisms. To provide a more definitive conclusion about their association with the risk of HCV infection, a meta-analysis was performed by combining and summarizing a total of 17 studies. A biological justification for the choice of genetic model was provided. The results indicated no significant association between these IL-10 polymorphisms and the susceptibility to HCV infection [–592C/A: odds ratio (OR) 0·99, 95% confidence interval (CI) 0·78–1·25; –819C/T: OR 0·90, 95% CI 0·69–1·18; –1082G/A: OR 1·34, 95% CI 0·90–2·00]. However, this analysis did not account for the possible risk modifications by other factors, such as ethnicity and virus persistence. Therefore, the effects of ethnicity and virus persistence were investigated using Bayesian meta-regression and subgroup analysis. Finally, an extended case-control association study was conducted in a Chinese population involving 1140 subjects. Both serum level and genotype data of IL-10 −1082G/A were determined. As a result, a low prevalence of G allele was observed. Significantly higher IL-10 production was observed in HCV patients, especially patients with the GG genotype.