NK cells require an intact bone marrow microenvironment to acquire lytic function. In mice rendered osteopetrotic by 17beta-estradiol treatment, NK1.1 positive cells are arrested in a nonlytic state. Culture with as little as 2 ng/ml of murine IL-15 (mIL-15), a cytokine produced by macrophages and stromal cells, causes these immature NK1.1+ cells to acquire lytic activity. By contrast, approximately 10- to 50-fold greater amount of mIL-2 was required to induce similar level of cytotoxicity. After culture with mIL-15, the relatively low expression of B220, CD11b, and Ly-49 molecules on immature NK1.1+ cells was increased to levels comparable to those of mature splenic NK1.1+ cells. mIL-15 also caused a greater expansion of NK1.1+CD3- cells as compared with NK1.1+CD3+ cells. We conclude that IL-15 is a specific maturation factor for NK cells and that it can mimic the marrow microenvironment in vitro.