In the induction of an immune response, IL-15Rα on APCs transpresents IL-15 to NK and CD8+/CD44 high T cells that express the IL-2/15Rβ and γc subunits only. In this study, we show data mimicking this transpresentation by using IL-15 preassociated with a chimeric protein that is comprised of the extracellular domain of murine IL-15Rα and the Fc portion of human IgG1. When tested in vitro, IL-15Rα-IgG1-Fc strongly increased the IL-15-mediated proliferation of murine NK and CD8+/CD44 high T cells. The effect of IL-15Rα-IgG1-Fc was dependent on the presence of both IgG1-Fc and IL-15Rα. When injected into mice, IL-15Rα-IgG1-Fc enhanced the capacity of IL-15 to expand the number of NK and CD8+/CD44 high T cells. The effect on cell numbers in vivo also depended on Fc receptor binding because reduced expansion was observed in FcRγ−/− mice. NK cells cultured in IL-15/IL-15Rα-IgG1-Fc complex gained cytotoxic activity toward a number of NK-sensitive targets. When mice bearing the NK-sensitive syngeneic tumor B16 were treated, the presence of IL-15Rα-IgG1-Fc increased the antitumor activity of IL-15. Thus, a preassociation with IL-15Rα-IgG1-Fc enhances the activities of IL-15 in vivo and in vitro that may be useful in the treatment of tumors.