During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56^bright and CD56^dim). In this report, it is shown that CD56^bright NK cells produce significantly greater levels of interferon-γ, tumor necrosis factor-β, granulocyte macrophage–colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56^dim NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56^bright NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine production by CD56^bright NK cells. It is proposed that human CD56^bright NK cells have a unique functional role in the innate immune response as the primary source of NK cell–derived immunoregulatory cytokines, regulated in part by differential monokine production.