Pretreatment up‐regulation of hepatic interferon (IFN)‐stimulated genes (ISGs) has a stronger association with the treatment‐resistant interleukin (IL)28B minor genotype (MI; TG/GG at rs8099917) than with the treatment‐sensitive IL28B major genotype (MA; TT at rs8099917). We compared the expression of ISGs in the liver and blood of 146 patients with chronic hepatitis C who received pegylated IFN and ribavirin combination therapy. Gene expression profiles in the liver and blood of 85 patients were analyzed using an Affymetrix GeneChip (Affymetrix, Santa Clara, CA). ISG expression was correlated between the liver and blood of the MA patients, whereas no correlation was observed in the MI patients. This loss of correlation was the result of the impaired infiltration of immune cells into the liver lobules of MI patients, as demonstrated by regional gene expression analysis in liver lobules and portal areas using laser capture microdissection and immunohistochemical staining. Despite having lower levels of immune cells, hepatic ISGs were up‐regulated in the liver of MI patients and they were found to be regulated by multiple factors, namely, IL28A/B, IFN‐λ4, and wingless‐related MMTV integration site 5A (WNT5A). Interestingly, WNT5A induced the expression of ISGs, but also increased hepatitis C virus replication by inducing the expression of the stress granule protein, GTPase‐activating protein (SH3 domain)‐binding protein 1 (G3BP1), in the Huh‐7 cell line. In the liver, the expression of WNT5A and its receptor, frizzled family receptor 5, was significantly correlated with G3BP1. Conclusions: Immune cells were lost and induced the expression of other inflammatory mediators, such as WNT5A, in the liver of IL28B minor genotype patients. This might be related to the high level of hepatic ISG expression in these patients and the treatment‐resistant phenotype of the IL28B minor genotype. (Hepatology 2014;59:828–838)