The pineal hormone melatonin has been used in clinical trials in patients suffering from AIDS and also as an adjuvant for cancer therapy. Although melatonin has been reported to have beneficial effects in some animal models of immune dysfunction, it remains unknown whether this hormone has any salutary effects on immunity following soft-tissue trauma and/or major blood loss. To study this, soft-tissue trauma (2.5-cm midline laparotomy) and hemorrhagic shock (arterial BP 35 ± 5 mm Hg) were induced in C3H/HeN mice. The mice were resuscitated after 90 min of hypotension with the shed blood and lactated Ringer's solution. Treatment with saline, vehicle, or melatonin (10 mg/kg BW) subcutaneously was administered in the evening of the day of surgery and again on the following evening. All animals were sacrificed at 48 hr following trauma-hemorrhage and resuscitation to obtain plasma, splenocytes, as well as splenic and peritoneal macrophages (M∅). The results indicate that melatonin administration after trauma-hemorrhage significantly improved the depressed immune functions, as evidenced by the restoration of Me IL-1 and IL-6 release, as well as significantly improved splenocyte IL-2 and IL-3 release and splenocyte proliferative capacity. No differences in circulating corticosterone levels between vehicle- and melatonin-treated animals were observed. This is the first study to show that melatonin, which is reported to be free of adverse side effects, can be considered a safe and effective therapeutic agent for restoring the depressed immunological function after soft-tissue trauma and hemorrhagic shock.