Chronic hepatitis C (CHC) is a worldwide health problem that is highly related to liver fibrosis, cirrhosis, and hepatocellular carcinoma. The achievement of response to the current standard of care—pegylated interferon plus ribavirin—has recently been described to be associated with single‐nucleotide polymorphisms (SNPs) near the IL‐28B gene. Additionally, baseline expression levels of genes involved in interferon (IFN)‐stimulated genes (ISGs) have been found to be related to treatment outcome. In the present study, 285 patients were genotyped for 63 SNPs within genes of the IFN signaling pathway (IPGs) and ISGs. Two ISG polymorphisms—OASL rs12819210 (odds ratio (OR) = 2.1, P = 0.03) and IFIT1 rs304478 (OR = 2.5, P = 0.01)—were found to be independent predictive factors of sustained virological response (SVR) after adjusting for other clinical covariates. Furthermore, the predictive value of IL‐28B SNP was notably improved by simultaneous genotyping of rs12819210 and rs304478, particularly in patients with the worst prognosis (viral genotype 1, area under the curve (AUC) = 0.74). In conclusion, ISG SNPs could constitute a valuable tool for individualizing CHC therapy. Clinical Pharmacology & Therapeutics (2011); 90 5, 712–721. doi:10.1038/clpt.2011.189