IL-15 is a newly described cytokine produced by monocytes and other non-T cells that utilizes the IL-2R beta- and common gamma-chains, thereby stimulating many NK cell functions previously ascribed to IL-2. Thus, IL-15 may promote NK cell activity during innate immune responses, before the activation of T lymphocytes and subsequent production of IL-2. This study investigated the ability of rIL-15 to substitute for rIL-2 in initiating proliferation of resting human NK cells cocultured with various stimulator cells. NK cell proliferation could not be initiated with rIL-15 as the sole costimulatory cytokine. However, NK cell proliferation was initiated with rIL-15 and either rIL-10 or rIL-12, cytokines also produced by monocytes and other APC and implicated in innate immune responses. Individually, rIL-10, rIL-12, and rIL-15 are effective initiators of NK cell proliferation when combined with submitogenic concentrations of rIL-2, indicating their potential involvement in NK cell proliferation at early stages of an Ag-specific T cell immune response. NK cells proliferating in the different cytokine combinations or optimum concentrations of rIL-2 were indistinguishable in terms of phenotype and cytotoxic activity, but differed in whether they secreted IFN-gamma or IL-5. IFN-gamma was secreted in cultures containing rIL-12, whereas IL-5 secretion was dependent upon interaction of IL-2 with the high affinity IL-2R. These results support the notion that NK cell proliferation occurs at different phases of the immune response with the particular cytokine milieu influencing the repertoire of NK cell-secreted cytokines.