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Background and Aims: HCV GT-3 has a more pronounced effect on hepatic steatosis and host lipids than other HCV genotypes and is proving less responsive to all oral interferon-free treatment with direct acting antiviral agents. As both HCV GT3 infection and NASH can result in steatosis and cirrhosis, we asked whether hepatic transcriptional profiles reflective of the host response to inflammation differed based on the etiology of injury., Methods: Hepatic gene expression was determined for 48 pre-selected genes known to be associated with hepatic interferon signaling and lipid metabolic pathways in treatment-naïve HCV GT-3 (n = 9) and NASH (n = 14) patients., Results: Genes with significantly higher expression in HCV included chemokines CXCL10, CXCL11 interferon IFNA2, interferon receptors IFNAR1, IL10RB negative regulators of interferon signaling SOCS3, USP18, JAK/STAT and IRF family members STAT1, STAT2, and IRF, and TGFB family members TGFB1, TGFBR1, and TGFBR2 and other ISGs like OAS2, IF127, IF144 and ISG15. HCV infection was also associated with higher expression of genes associated with lipid metabolism APOE, APOL3, SREBF1 and HMBS. Furthermore, our results suggest that, in HCV GT3-infected patients, IL28B (CC) genotype is associated with lower baseline ISG expression such as IRF9, ISG15, MX1, STAT1, CXCL10, CXCL11, and IFI27 compared to CT/TT genotype., Conclusions: HCV GT-3 and NASH both induce hepatic steatosis and inflammation, while HCV GT-3 infection is uniquely associated with elevated transcription of hepatic ISGs and genes associated with lipid metabolism. These changes likely reflect the unique host response to HCV replication distinct from the inflammatory response induced by NASH.