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 α (TNF-α) 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-α 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 (ORcrude = 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) − (−2575T) − (−2763C) − (−1082A) − (−819T) − (−592A) is associated with SR to IFN + R.