Background: The global prevalence of chronic hepatitis C is estimated at 2.8%. There is markedly higher prevalence in the Middle East about 14.7% in Egypt. Dendritic cells (DCs) are one of the major Antigen presenting cells in the body. They bridge innate and adaptive immunity and impact priming of HCV-specific immune responses. The current study was aimed to investigate the DC activation status, and their role in interaction with natural killer (NK) cells utilizing different setups with healthy NK and HCV⁺ DC, HCV⁺ NK and healthy DC, healthy DC and healthy NK and finally HCV⁺ NK and HCV⁺ DC in the presence of HCV peptides and a ratio of 5 NK: 1DC. Results: DC-NK interaction in chronic HCV infection is mainly affected by the affection of DCs by HCV leading to a maturation defect (decreased expression of HLA DR, CD 86 and CD 83). Healthy NK cells were able to stimulate the maturation of DCs particularly with core peptide whereas NS3-4 had no effect. When DCs were healthy, all peptides were able to produce significant maturation of DCs even when co-cultured with HCV⁺ NK cells. Co-cultured HCV⁺ NK cells and HCV⁺ DCs showed significantly higher apoptosis of both cells. This could be attributed to the immature moDCs more with chronic HCV infection due to the fact that immature DCs typically under express HLA-class I molecules that would protect from NK-mediated lysis. Conclusion:   Cross-talk between DCs and NK cells plays an important role in the induction of both the innate and adaptive immune systems. HCV infection was found to impair the maturation of DCs. Thus consequently affecting its antigen presentation and T cell allostimulatory capacity and rendering them more liable to NK mediated lysis which could explain the persistence of infection and chronicity.