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Background and Aims: The failure of HCV-specific CD8 T-cells is linked to the development of chronic infection. However, the responsible mechanisms are only partly understood. The initial priming of CD8 T-cells is key for the induction of immune responses. Studies have shown an important role of the cytokine interleukin-10 (IL-10) in HCV-infection. Thus, we analyzed whether IL-10 affects the initial priming of HCV-specific CD8 T-cells. Methods: To address this important question, we performed in vitro priming experiments of naive HCV-specific CD8 T-cells from healthy donors by using autologous monocyte-derived dendritic cells (MD-DCs) in the presence or absence of IL-10. After 8 days of co-culture, frequency, phenotype and function of HCV-specific CD8 T-cells were analyzed. Results: The presence of IL-10 during priming significantly reduces the frequency of HCV-specific CD8 T-cells after 8 day proliferation. To identify the target cells of IL-10 action, we performed separate pre-incubations of MD-DCs and CD8 T-cells with IL-10. These results revealed that IL-10 acts directly on CD8 T-cells. Interestingly, HCV-specific CD8 T-cells primed in the presence of IL-10 also showed signs of impaired differentiation into effector cells. In contrast to the suppressive effect of IL-10 during priming, addition of IL-10 at day 4 after priming had no inhibitory but rather stimulatory activity on HCV-specific CD8 T-cell proliferation. Conclusions: In sum, we could show a suppressive effect of IL-10 on the priming of naive HCV-specific CD8 T-cells. This provides a mechanistic basis for the clinical observation, that high IL-10 levels in the acute phase of infection are associated with the progression to chronicity.