Serum levels of interleukin-10 (IL-10) are elevated in a proportion of patients with untreated chronic hepatitis C, and this may compromise the host immune response to the virus. The capacity for IL-10 production varies according to the genetic composition of the IL-10 locus. We examined the inheritance of 3 biallelic polymorphisms in the IL-10 gene promoter in patients with chronic hepatitis C and their association with response to treatment with interferon alfa (IFN-alpha). After adjusting for potential confounding variables, a highly significant relationship was found between inheritance of the IL-10 promoter -592*A and -819*T alleles or the ATA haplotype and response to IFN-alpha therapy (P =.016). Response to treatment was also associated with viral genotype 3a, a low viral load, and less fibrosis on liver biopsy. Following in vitro stimulation of peripheral blood mononuclear cells, the IL-10 promoter haplotypes, GCC, ACC, and ATA, were associated with high, intermediate, and low IL-10 production, respectively. These findings indicate that heterogeneity in the promoter region of the IL-10 gene has a role in determining the initial response of chronic hepatitis C to IFN-alpha therapy. Patients who are genetically predisposed to high IL-10 production have a poor response to IFN-alpha and may benefit from additional treatment strategies designed to enhance a T-helper type 1 (Th1) response.