IL-10 is an immunomodulatory cytokine that acts to antagonize T cell responses elicited during acute and chronic infections. Thus, the IL-10R signaling pathway provides a potential therapeutic target in strategies aimed at combating infectious diseases. In this study, we set out to investigate whether IL-10 expression had an effect on NK cells. Murine CMV infection provides the best characterized in vivo system to evaluate the NK cell response, with NK cells being critical in the early control of acute infection. Blockade of IL-10R during acute murine CMV infection markedly reduced the accumulation of cytotoxic NK cells in the spleen and lung, a phenotype associated with a transient elevation of virus DNA load. Impaired NK cell responsiveness after IL-10R blockade was attributed to elevated levels of apoptosis observed in NK cells exhibiting an activated phenotype. Therefore, we conclude that IL-10 contributes to antiviral innate immunity during acute infection by restricting activation-induced death in NK cells.