The reasons for hepatitis C treatment failure remain unknown but may be related to different host responses to therapy. In this study, we compared hepatic gene expression in patients prior to and during peginterferon and ribavirin therapy. In the on‐treatment group, patients received either ribavirin for 72 hours prior to peginterferon alpha‐2a injection or peginterferon alpha‐2a for 24 hours, prior to biopsy. The patients were grouped into rapid responders (RRs) with a greater than 2‐log drop and slow responders (SRs) with a less than 2‐log drop in hepatitis C virus RNA by week 4. Pretreatment biopsy specimens were obtained from a matched control group. The pretreatment patients were grouped as RRs or SRs on the basis of the subsequent treatment response. Gene expression profiling was performed with Affymetrix microarray technology. Known interferon‐stimulated genes (ISGs) were induced in treated patients. In the pretreatment group, future SRs had higher pretreatment ISG expression than RRs. On treatment, RRs and SRs had similar absolute ISG expression, but when it was corrected for the baseline expression with the pretreatment group, RRs showed a greater fold change in ISGs, whereas SRs showed a greater change in interferon (IFN)‐inhibitory pathways. The patients pretreated with ribavirin had heightened induction of IFN‐related genes and down‐regulation of genes involved in IFN inhibition and hepatic stellate cell activation. Conclusion: These data suggest that ISG inducibility is important for the treatment response and that ribavirin may improve outcomes by enhancing hepatic gene responses to peginterferon. Collectively, these mechanisms may provide a molecular basis for the improved efficacy of combination therapy. (HEPATOLOGY 2007.)