More interleukin 15 (IL-15) than IL-2 was needed to generate comparable proliferative responses by phytohaemagglutinin (PHA) blasts and Tf-1β cells expressing high affinity and intermediate affinity IL-2 receptor (IL-2R) complexes, respectively. The focus of these experiments was to determine the contribution of the shared IL-2 and IL-15 receptor components to these dose-response differences. Some of this difference can be attributed to the role of the IL-2Rβ chain, in that HuMikβ1, a monoclonal antibody recognizing the IL-2Rβ chain, blocks 92.2±2.5% (mean±SE) of the IL-2 proliferative response by Tf-1β cells but only inhibits 57.9±3.7% of the IL-15 response, indicating that IL-2 and IL-15 may physically utilize the IL-2Rβ chain differently. Monoclonal antibody 341, which recognizes IL-2Rβ but does not inhibit IL-2 binding to the IL-2Rβ chain, blocks 35.4±2.3% of IL-15-stimulated proliferation of PHA blasts, while not affecting the IL-2-stimulated proliferation. Finally, although HuMikβ1 does not inhibit IL-2 responses by PHA blasts bearing high affinity IL-2 receptors, HuMikβ1 does block IL-15-stimulated proliferation by these same cells bearing high affinity IL-15 receptors (88.5±1.6% inhibition). This indicates that the role of IL-15Rα in the high affinity IL-15R complex is distinct from that of IL-2Rα in the high affinity IL-2R complex. Overall, these studies show that the physical interactions of the IL-2Rβγ_ccomplex with IL-2 are different than the interactions with IL-15.