Background: HCV infection results in hepatocellular carcinoma. mTORC1 and eIF4E regulate tumorigenesis through translation initiation. Results: HCV, through NS5A, activates mTORC1 and eIF4E, resulting in enhanced eIF4F assembly. NS5A binds to eIF4F complex and associates with polysomes. Conclusion: HCV up-regulates cap-dependent host protein translation machinery through NS5A. Significance: Activation of host translation machinery might facilitate HCV-associated hepatocellular carcinoma.