A G-to-A polymorphic sequence at position -308 in the tumor necrosis factor alpha promoter (TNF308.2) might be associated with disease susceptibilities. To investigate the association between -308 TNF-alpha variants and pathogenesis of hepatitis C virus (HCV) infection and response to interferon-alpha (IFN-alpha) treatment for chronic hepatitis C (CHC), -308 TNF-alpha genotypes were determined in 100 unrelated Taiwanese CHC patients treated with IFN-alpha and in 100 unrelated healthy subjects. The distribution of -308 TNF-alpha genotypes did not differ between CHC patients and controls. Age, sex, HCV genotype, and the necroinflammatory activity of liver histopathology did not differ among CHC patients with different -308 TNF-alpha genotypes. Although pretreatment HCV RNA serum levels, aminotransferase and the rate of severe fibrosis decreased with the copy number of TNF308.2, the difference did not reach significance. We failed to demonstrate any association between -308 TNF-alpha promoter polymorphisms and response to IFN therapy, which was inversely correlated to liver cirrhosis, pretreatment serum HCV RNA levels and genotype 1b by using multivariate analysis. In conclusion, our findings suggest that -308 TNF-alpha promoter polymorphisms do not play a direct role in the susceptibility and pathogenesis of HCV infection, and in the response to interferon-alpha therapy for CHC.