Natural killer ( NK ) cells through their NK group 2 member D ( NKG 2D) receptors recognize NKG 2D ligands such as UL 16‐binding proteins ( ULBP s) on virus‐infected cells and subsequently trigger the host innate immune response. In the present study, we demonstrated that hepatitis C virus ( HCV ) induced the cell surface expression of ULBP 1 in human immortalized hepatocyte PH 5 CH 8 cells and human hepatoma HuH‐7 cell‐derived RS c cells. Interestingly, NK cell line NK ‐92 induced cytotoxicity and interferon‐γ mRNA expression and subsequently reduced the levels of HCV RNA replication during co‐culture with HCV ‐infected RS c cells. From these results, we conclude that ULBP 1 is a target of the NK cell‐mediated innate immune response in HCV ‐infected human hepatocytes.