Melatonin administration has been reported to have beneficial effects on immune function in some clinical studies and in several animal models of immune dysfunction. Furthermore, recent studies suggest beneficial effects of melatonin on depressed immune function following trauma-hemorrhage. Nonetheless, it remains unknown whether this hormone has any salutary effects on survival following hemorrhagic shock and subsequent septic challenge. Male C3H/HeN mice were bled to and maintained at a mean arterial blood pressure of 35 ± 5 mm Hg for 90 min, adequately resuscitated, and 48 hr thereafter subjected to sepsis (cecal ligation and puncture; CLP). Melatonin-treated mice received either short-term treatment on Days 1 and 2 after hemorrhage or continuous treatment throughout the study. Treatment with vehicle (10% ethanol in normal saline) or melatonin (10 mg/kg body weight) was administered daily starting in the evening of the day of hemorrhage/sham-operation. Short-term melatonin administration after hemorrhage significantly improved survival in animals subjected to septic challenge. Continuous melatonin treatment did not improve survival, as compared to vehicle-treated mice subjected to shock and CLP. Moreover, continuous melatonin treatment in sham-operated animals significantly increased mortality compared to short-term-treated and vehicle-treated animals. While the mechanisms of the differential effects of melatonin administration are yet to be clearly defined, this study, nonetheless, demonstrates the salutary effects of short-term melatonin administration in the treatment of immune dysfunction following hemorrhagic shock.