Abstract: Background: The mechanisms by which interferon‐γ (IFN‐γ) contributes to inter‐individual heterogeneity in the severity of chronic hepatitis C (CH‐C) are unknown. In 116 consecutive patients with CH‐C, we tested the hypothesis that host genetic factors regulating IFN‐γ production and activity influence the severity of liver damage and hepatitis C virus (HCV)‐specific T‐cell reactivity.Methods: We determined the genotypes of functionally significant polymorphisms in the IFN‐γ gene and in the promoter of interleukin‐10 (IL‐10), a cytokine that counteracts IFN‐γ. We also measured concanavalin A (Con A)‐stimulated IL‐10 and IFN‐γ production, and the frequency of virus‐specific T‐cells, producing IFN‐γ or IL‐10.Results: The grade of inflammation and the stage of fibrosis of CH‐C showed no associations with either the IFN‐γ or IL‐10 promoter polymorphisms or with Con A‐stimulated IL‐10 or IFN‐γ production. Similarly, there were no associations between HCV‐specific T‐cell frequencies and these host genetic factors. On multivariate analysis, the grade of inflammation and the duration of HCV infection accounted for only 37% of the variance in the stage of CH‐C (P<0.0001). This percentage did not increase by including any genetic variables in the analyses.Conclusion: Future studies investigating the entire cytokine gene sequences will provide better information regarding genetic variations responsible for inter‐individual differences in the severity of CH‐C.