Abstract IFN-γ emanating from NK cells is an important component of innate defense against infection. In this study, we demonstrate that, following in vitro stimulation of human peripheral blood NK cells with a variety of microbial ligands, CD56dim as well as CD56bright NK cells contribute to the overall NK cell IFN-γ response with, for most cell donors, IFN-γ+ CD56dim NK cells outnumbering IFN-γ+ CD56bright NK cells. We also observe that the magnitude of the human NK IFN-γ response to microbial ligands varies between individuals; that the antimicrobial response of CD56bright, but not CD56dim, NK cells is highly correlated with that of myeloid accessory cells; and that the ratio of IFN-γ+ CD56dim to IFN-γ+ CD56bright NK cells following microbial stimulation differs between individuals but remains constant for a given donor over time. Furthermore, ratios of IFN-γ+ CD56dim to IFN-γ+ CD56bright NK cells for different microbial stimuli are highly correlated and the relative response of CD56dim and CD56bright NK cells is highly significantly associated with killer Ig-like receptor (KIR) genotype. These data reveal an influence of KIR genotype, possibly mediated via NK cell education, on the ability of NK cells to respond to nonviral infections and have implications for genetic regulation of susceptibility to infection in humans.