The IL-2R is composed of at least two subunits, the p55 (CD25/Tac) and p75 glycoproteins. The p75 IL-2R is expressed preferentially on resting human peripheral blood NK cells, but is not detected on substantial proportions of T and B lymphocytes, monocytes, or granulocytes. Anti-p75 IL-2R mAb substantially inhibits the early events associated with NK cell activation by IL-2, including inhibition of cytotoxic activity and induction of the CD69 early activation antigen. While anti-p55 IL-2R mAb alone failed to substantially inhibit the initial events of IL-2 stimulation, maximal inhibition of IL-2-induced cytotoxicity and proliferation was achieved by combining both anti-p55 IL-2R and anti-p75 IL-2R. Collectively, results from the present studies directly implicate the p75 IL-2R as the structure predominantly responsible for IL-2 activation of NK cells.