The methionine-enkephalin (Met-enkephalin, Tyr-Gly- Gly-Phe-Met) analogs Tyr-D-Ala-Gly-MePhe-Met NHC(3)H(7)-iso (1) and Tyr-D-Ala-Gly-MePhe-Gly-NHC(3)H(7)-iso (2) have been shown to enhance human T cell proliferation in in vitro treatment. Their immunomodulatory activities were completely blocked by naloxone, an opioid antagonist. Now we demonstrate that a selective delta-opioid receptor antagonist, ICI-174,864, completely blocks enhancement of T cell proliferation by analogs (1) and (2). The T cell-stimulatory effect was only partially inhibited by the mu-receptor-selective antagonist, beta-funaltrexamine hydrochloride. The kappa-opioid receptor antagonist, nor-binaltorphimine dihydrochloride, showed no effect on T cell-proliferation stimulated by analogs (1) and (2). These observations suggest that analogs (1) and (2) of Met-enkephalin stimulate T cell proliferation predominantly via delta-opioid receptor present on T cells.