The effects of acutely-administered morphine on mitogen stimulated lymphocyte proliferation and natural killer cell cytolytic activity were investigated. Two hours after a subcutaneous injection of morphine (25 mg/kg), blood lymphocyte proliferation was found to be 70% depressed, compared to saline-injected controls. This effect was partially antagonized in animals pretreated with naltrexone (10 mg/kg) and was present only in blood lymphocytes, since proliferative responses of splenic lymphocytes were not significantly altered. The administration of morphine, however, did result in a 30-40% inhibition of cytolytic activity of natural killer cells, which was completely antagonized in naltrexone-pretreated animals. Naltrexone alone was found to have no effect on either proliferation of blood and splenic lymphocytes or the cytolytic activity of splenic lymphocytes. Although naltrexone had no effect on the activity of lymphocytes, animals treated with either naltrexone or morphine alone, or their combination, had 4- to 8-fold increases in corticosterone in plasma. These results demonstrate that the effect of morphine on immune cells was dependent on the tissue source of lymphocytes. Furthermore, the suppression of blood lymphocyte proliferation and splenic cytolytic activity of natural killer cells by morphine was opiate receptor-mediated, as indicated by the reversibility by naltrexone of the observed effects of morphine. Finally, the accompanying increase in circulating levels of corticosterone most likely did not contribute to these effects.