Natural killer (NK) cells are large granular lymphocytes thought to be important in the host's early immune response to viral infection and malignant transformation. NK cells proliferate and display enhanced cytotoxic activity in response to the T cell growth factor, interleukin 2 (IL-2). Stem cell factor or steel factor (SF) is the ligand for the c-kit receptor, and when combined with other hematopoietic growth factors, SF synergistically promotes the proliferation and differentiation of bone marrow stem cells. In the present study we show the c-kit receptor to be uniquely expressed on a subset of resting human NK cells (CD56bright) which constitutively expresses both the high affinity IL-2 receptor (IL-2R) and the intermediate affinity IL-2R. Other lymphocyte populations, including CD56dim NK cells, did not appear to express the c-kit receptor. Within the CD56bright NK cell subset, SF alone had no obvious effect on proliferation or cytotoxic activity. SF was shown to significantly augment the proliferative effect of IL-2, and caused a marked shift in the dose-response curve at IL-2 concentrations that selectively saturate the high affinity IL-2R. The potentiating effect of SF on NK cell proliferation was dependent on IL-2 binding to the high affinity IL-2R, and was blocked by a monoclonal antibody directed against the c-kit receptor. SF did not enhance proliferation at higher IL-2 concentrations that saturate the intermediate affinity IL-2R, nor did SF enhance IL-2-induced cytotoxic activity. Together, these data indicate that SF and IL-2 act synergistically to directly augment the proliferative capacity of a unique human NK cell subset constitutively expressing the high affinity IL-2R and the c-kit receptor. The implications of these findings on NK cell development and the host's early immune response to pathogen invasion are discussed.