The purpose of the present study was to determine the potential consequences to the immune system of the combined exposure of rats to stressor and morphine. Within 30 min following either morphine (5 mg/kg) injection or restraint stress (30 min) maximal analgesic responses as measured by tail-flick assay were observed. However, only morphine treatment was accompanied by a significant suppression (50%) in mitogen-stimulated lymphocyte proliferative responses. Restraint stress for either a 30-min or 2-h duration had no effect on lymphocyte responses. Exposure to a combination of restraint stress and acute morphine (5 mg/kg) resulted in a 50% suppression of lymphocyte responses which was similar in magnitude to that observed with morphine administration alone. When rats were injected twice daily for 4 days with increasing doses of morphine ranging from 10 mg/kg to 40 mg/kg, morphine (10 mg/kg) administration on Day 5 was not accompanied by either analgesia or depressed blood lymphocyte proliferative responses. These results indicated that tolerance had developed to both the analgesic and the immunosuppressive effects of morphine. However, upon exposure of morphine-tolerant animals to restraint stress, significant analgesic responses were retained. Furthermore, in contrast to the lack of suppression following restraint stress on lymphocyte responses in saline-injected animals, restraint for 30 min produced greater than a 70% suppression in morphine-tolerant animals. These data suggest that morphine tolerance may be accompanied by an enhanced susceptibility to the immunosuppressive effects of stress.