In this study, we demonstrate that human NK cells, human NK clones, the human NK cell line (NK3.3), and a population of murine NK cells can produce the type 2 cytokine IL-13 in response to IL-2 or phorbol myristate acetate plus ionomycin. IL-2 rapidly induced new IL-13 mRNA and protein synthesis in the NK3.3 cell line. Six of 12 human NK clones tested produced IL-13 protein in response to IL-2 or phorbol myristate acetate and ionomycin. Intracellular analysis revealed that approximately 2% of human peripheral NK cells produced IL-13 protein in response to IL-2. Isolated NK cells from SCID and RAG-2 knockout (-/-) mice that lack T and B cells as well as normal mice also can produce IL-13 mRNA and protein in response to IL-2. We hypothesized that in the absence of IFN-gamma, IL-13-producing NK cells may predominate in vivo. Utilizing IFN-gamma knockout (-/-) mice as a model system, IL-2-activated liver NK and T cells expressed 10-fold more IL-13 and IL-5 mRNA and protein than normal controls following IL-2 treatment in vitro. These results suggest that in the absence of IFN-gamma, an IL-13- and IL-5-producing NK and T cells predominate in vivo. The existence of this cell type has important implications in innate immunity given that the balance between IFN-gamma and IL-13/IL-5-producing NK cells may influence the early development of a cell-mediated or humoral immune response.