Background: Hepatitis C is a viral infection of the liver that has affected around 200 million people globally. The immune response against HCV infection includes both the innate and adaptive arms of immunity, with crosstalk between liver inhabitant and infiltrating cells. In the current study, we aimed to investigate the natural killer cells activation and inhibition status, and their role in interaction with DCs utilizing different combinations between NK cells and DCs in the presence of HCV peptides in a ratio of 5 NK: 1DC.Results: HCV NK cells upregulated both activation and inhibition markers. This could be attributed to HCV infection and their interaction with DCs especially healthy DCs.  Moreover, apoptosis of DCs and NK cells occurred more in HCV NK cultures due to their higher frequency of NKp30 and KLRG1. The death of NK cells was more than DCs despite DCs maturation defect due to HCV infection, suggesting that the inhibitory marker KLRG1 took the upper hand over the upregulated activation markers leading to impaired cytotoxic activity and apoptosis of NK cells. Conclusion: The bidirectional crosstalk between NK cells and DCs is important in both potentiating mechanisms of the innate immune responses and the subsequent adaptive immune responses in the immune surveillance of cancer and infections. HCV infection impairs this crosstalk which may be a leading cause in viral persistence and chronicity.