The G-->A transition in the tumor necrosis factor (TNF)- alpha promoter region at position -308 (TNF308.2) and -238 (TNF238.2) were determined in 141 patients with chronic hepatitis C virus (HCV) infection. Patients received combination therapy with high-dose interferon (IFN)- alpha and ribavirin for 24 weeks. A total of 100 patients (70.9%) had a sustained virologic response (SVR) after treatment. The TNF308.2 allele was independently associated with an SVR, particularly in patients with HCV genotype 1b infection and >200,000 IU of HCV RNA/mL in serum. In conclusion, the response to combination therapy with high-dose IFN- alpha and ribavirin may be associated, at least in part, with host genetic factors.