Natural killer (NK) cells are a major component of the host innate immune defense against various pathogens. Several viruses, including hepatitis C virus (HCV), have developed strategies to evade the NK-cell response. In our study, we found HCV infection could trigger DNA damage response by both ataxia telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) pathways. Recent reports had revealed that NKG2D ligands (NK cell-activating ligands) were upregulated when a major DNA damage checkpoint pathway was activated. However, here we found that DNA damage response was activated but NKG2D ligands were downregulated upon HCV infection. Further studies showed that the protease NS3/4A of HCV which had been shown relation with immune invasion contributed to the reduced expression of NKG2D ligands. These findings provide a novel insight into the mechanisms evolved by HCV to escape from the NK cell response. Several viruses, including hepatitis C virus (HCV), have developed strategies to evade the NK-cell response. In our study, we found that HCV infection could trigger DNA damage response by both at ATM and Rad3-related (ATR) pathways. Recent reports had revealed that NKG2D ligands (upregulated NK cell-activating ligands) were upregulated when a major DNA damage checkpoint pathway was activated However, here we found that DNA damage response was activated but NKG2D ligands were downregulated upon HCV infection. These studies showed that the protease NS3 / 4A of HCV had had been shown with immune invasion contributed to the reduced expression of NKG2D ligands. These findings provide a novel insight into the mechanisms evolved by HCV to escape from the NK cell response.