IL-15 is normally presented in vivo as a cell-associated cytokine bound to IL-15Rα. We show here that the biological activity of soluble IL-15 is much improved after interaction with recombinant soluble IL-15Rα; after injection, soluble IL-15/IL-15Rα complexes rapidly induce strong and selective expansion of memory-phenotype CD8⁺ cells and natural killer cells. These findings imply that binding of IL-15Rα to IL-15 may create a conformational change that potentiates IL-15 recognition by the βγ_c receptor on T cells. The enhancing effect of IL-15Rα binding may explain why IL-15 normally functions as a cell-associated cytokine. Significantly, the results with IL-2, a soluble cytokine, are quite different; thus, IL-2 function is markedly inhibited by binding to soluble IL-2Rα.