Host genetic factors have been reported to influence the natural history of hepatitis C virus (HCV) infection. We examined whether variation in interleukin 10 (IL-10) and tumor necrosis factor ␣ (TNF-␣) genes would predict the likelihood of sustained response to antiviral therapy. Single nucleotide polymorphisms (SNPs) and microsatellites at two loci encoding the cytokines IL-10 and TNF-␣ were determined by polymerase chain reaction (PCR)-based techniques. Their relationship to the outcome of antiviral therapy for chronic HCV infection was studied in 49 white patients who had a virologically sustained response (SR) and in 55 white nonresponders (NR) to a combination of interferon alfa-2b and ribavirin (IFN ؉ R). Several IL-10 variants were more frequent among SRs compared with NRs. Carriage of the ؊592A or the ؊819T SNP was associated with SR (odds ratio [OR] ؍ 2.2; P ؍ .016). The ؊592A/A and the exclusively linked ؊819T/T genotypes were also associated with SR (OR ؍ 16.6; P ؍ .013 for either). The haplotype consisting of the 108-bp IL-10.R microsatellite and ؊3575T, ؊2763C, ؊1082A, ؊819T, ؊592A was also associated with SR (OR ؍ 2.65; P ؍ .01). Stratification for viral genotype, baseline viral RNA concentration, and histologic status identified homozygosity for the haplotype as the principal determinant: all 5 homozygous individuals achieved SR (OR crude ؍ 13.7; P ؍ .025; stratified ORs ؍ 1.9-7.0), whereas heterozygotes differed only slightly from wild-type carriers. In contrast, TNF alleles defined by promoter sequences ؊238G/A and ؊308G/A were approximately equally distributed among SR and NR. In conclusion, homozygosity for ؊592A, ؊819T or the extended haplotype (108bp) ؊ ( During the last decade, treatment for hepatitis C virus (HCV) infection has rapidly improved. Interferon alfa-2b in combination with ribavirin (IFN ϩ R) has become the standard regimen for HCV infection. Sustained response (SR) to IFN ϩ R, defined as undetectable HCV RNA at 6 months after discontinuation of therapy, is achievable in 30% to 60% of treated patients.