The identification and cloning of the novel cytokine IL-15 were recently described. IL-15 is produced by a wide range of cell types, with the highest levels of IL-15 mRNA being detected in epithelial lines, monocytes, muscle, and placenta. Although it has no sequence identity with IL-2, IL-15 shares many of the T cell-stimulatory activities described for IL-2. We have examined IL-15 for its ability to stimulate B cells and have compared its activity with that of IL-2. IL-15 costimulates proliferation of B cells activated with immobilized anti-human IgM or phorbol ester, but has no stimulatory effect on resting B cells. In combination with recombinant CD40L, IL-15 is a potent inducer of polyclonal IgM, IgG1, and IgA secretion, but does not cause production of IgG4 or IgE. The activity of IL-15 in B cell proliferation and differentiation assays is comparable with that of IL-2. Studies that used neutralizing Abs have demonstrated that, for signal transduction in B cells, IL-15 uses the beta-chain of the IL-2R complex but, unlike IL-2, does not require the alpha-chain. IL-2 is required for the generation of a human primary Ag-specific in vitro response using sheep erythrocytes as Ag. Of all cytokines examined, only IL-15 has the capacity to replace IL-2 in this system, although only partially. In summary, IL-15 has comparable activity with IL-2 for the induction of B cell proliferation and differentiation and uses at least some of the components of the IL-2R complex to mediate its effects.