Met-enkephalin (Tyr-Gly-Gly-Phe-Met) and its more stable analogs, Tyr-D-Ala-Gly-MePhe-Met-NHC3H gamma-iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC3H gamma-iso (2) significantly enhanced human T-cell proliferation in vitro after 5 days of incubation in the absence of mitogen. The activity was completely inhibited by naloxone, an opioid antagonist. These peptides significantly enhanced human active T-cell rosette (CD2R) also on in vitro treatment. Furthermore, these analogs stimulated interleukin-2 production by human peripheral blood mononuclear cells in vitro which was completely inhibited by naloxone. These observations suggest that human T-cells bear receptors for Met-enkephalin on their surface. Such findings may provide a link between the central nervous system and the immune system.