Recent studies in mice have shown that although interleukin 15 (IL-15) plays an important role in regulating homeostasis of memory CD8⁺ T cells, it has no apparent function in controlling homeostatic proliferation of naive T cells. We here assessed the influence of IL-15 on antigen-independent expansion and differentiation of human CD8⁺ T cells. Both naive and primed human T cells divided in response to IL-15. In this process, naive CD8⁺ T cells successively down-regulated CD45RA and CD28 but maintained CD27 expression. Concomitant with these phenotypic changes, naive cells acquired the ability to produce interferon γ (IFN-γ) and tumor necrosis factor α (TNF-α), expressed perforin and granzyme B, and acquired cytotoxic properties. Primed CD8⁺ T cells, from both noncytotoxic (CD45RA^-CD27⁺) and cytotoxic (CD45RA⁺CD27^-) subsets, responded to IL-15 and yielded ample numbers of cytokine-secreting and cytotoxic effector cells. In summary, all human CD8⁺ T-cell subsets had the ability to respond to IL-15, which suggests a generic influence of this cytokine on CD8⁺ T-cell homeostasis in man. (Blood. 2003;102:2541-2546)