Human NK cells cultured in the presence of IL-12 or IL-4 differentiate into cell populations with distinct patterns of cytokine secretion similar to Th1 and Th2 cells. NK cells grown in IL-12 (NK1) produce IL-10 and IFN-γ, whereas NK cells grown in IL-4 (NK2) produce IL-5 and IL-13. Although these NK cell subsets do not differ in cytotoxic activity, NK1 cells express higher levels of cell surface CD95 (Fas) Ag than NK2 cells and are more sensitive to Ab or chemically induced apoptosis. Like Th1 cells, NK1 cells accumulate much higher levels of the IL-12Rβ2-chain mRNA and are significantly more responsive to IL-12 than NK2 cells at the level of activation of STAT4 transcription factor. The identification of NK cell subsets that are analogous to T cell subsets suggests a new role for NK cells in innate inflammatory responses and in their effect on adaptive immunity.