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Genetic variation in the IL28B (interleukin 28B; interferon lambda 3) region has been associated with sustained virological response (SVR) rates in patients with chronic hepatitis C (CHC) who were treated with peginterferon‐α and ribavirin. We hypothesized that IL28B polymorphism is associated with intrahepatic expression of interferon‐stimulated genes (ISGs), known to influence treatment outcome. IL28B genotyping (rs12979860) and whole‐genome RNA expression were performed using liver biopsies from 61 North American patients with CHC. After correction for multiple testing (false discovery rate < 0.10), 164 transcripts were found to be differentially expressed by IL28B‐type. The interferon signaling pathway was the most enriched canonical pathway differentially expressed by IL28B‐type (P < 10⁻⁵), with most genes showing higher expression in livers of individuals carrying the poor‐response IL28B‐type …