IL-15 is a cytokine that can affect many immune cells, including NK cells and CD8 T cells. In several tumor models, IL-15 delays primary tumor formation and can prevent or reduce metastasis. In this study, we have employed a model of breast cancer metastasis to examine the mechanism by which IL-15 affects metastasis. When breast tumor cells were injected i.v. into IL-15 2/2 , C57BL/6, IL-15 transgenic (TG) and IL-15/IL-15Ra-treated C57BL/6 mice, there were high levels of metastasis in IL-15 2/2 mice and virtually no metastasis in IL-15 TG or IL-15-treated mice. In fact, IL-15 2/2 mice were 10 times more susceptible to metastasis, whereas IL-15 TG mice were at least 10 times more resistant to metastasis when compared with control C57BL/6 mice. Depletion of NK cells from IL-15 TG mice revealed that these cells were important for protection from metastasis. When NK cells were depleted from control C57BL/6 mice, these mice did not form as many metastatic foci as IL-15 2/2 mice, suggesting that other cell types may be contributing to metastasis in the absence of IL-15. We then examined the role of CD4 T cells and macrophages. In IL-15 2/2 mice, in vivo depletion of CD4 T cells decreased metastasis. The lack of IL-15 in IL-15 2/2 mice, and possibly the Th2-polarized CD4T cells, was found to promote the formation of M2 macrophages that are thought to contribute to metastasis formation. This study reveals that whereas IL-15 effects on NK cells are important, it also has effects on other immune cells that contribute to metastasis.