Chronic hepatitis C (CHC) is associated with the development of metabolic disorders, including both hepatic and extra-hepatic insulin resistance (IR). Here, we aimed at identifying liver-derived factor(s) potentially inducing peripheral IR and uncovering the mechanisms whereby HCV can regulate the action of these factors. We found ANGPTL4 (Angiopoietin Like 4) mRNA expression levels to positively correlate with HCV RNA (r = 0.46, p < 0.03) and HOMA-IR score (r = 0.51, p = 0.01) in liver biopsies of lean CHC patients. Moreover, we observed an upregulation of ANGPTL4 expression in two models recapitulating HCV-induced peripheral IR, i.e. mice expressing core protein of HCV genotype 3a (HCV-3a core) in hepatocytes and hepatoma cells transduced with HCV-3a core. Treatment of differentiated myocytes with recombinant ANGPTL4 reduced insulin-induced Akt-Ser473 phosphorylation. In contrast, conditioned medium from ANGPTL4-KO hepatoma cells prevented muscle cells from HCV-3a core induced IR. Treatment of HCV-3a core expressing HepG2 cells with PPARγ antagonist resulted in a decrease of HCV-core induced ANGPTL4 upregulation. Together, our data identified ANGPTL4 as a potential driver of HCV-induced IR and may provide working hypotheses aimed at understanding the pathogenesis of IR in the setting of other chronic liver disorders.