We examined the effect of the pineal neurohormone melatonin (MLT) on protection from viral encephalitis. The antiviral activity of MLT was evaluated in normal mice inoculated with Semliki Forest virus (SFV) and in stressed mice injected with the attenuated non-invasive West Nile virus (WN-25). Administration of MLT (s.c.) daily from 3 days before through 10 days after virus inoculation reduced viremia and significantly postponed the onset of disease and death by 7 to 10 days. Moreover, MLT injection reduced mortality of SFV (10 PFU) inoculated mice from 100% to 44%. In mice inoculated with high dose of SFV (100 PFU), MLT postponed death and reduced mortality by 20%. In all of the surviving mice anti-SFV antibodies were detected 22 days after virus inoculation. Infection of mice stressed by either isolation or dexamethasone injection with WN-25 induced mortality of 75% and 50% respectively, which was reduced by MLT administration to 31% and 25%, respectively. The efficiency of MLT in protecting from lethal viral infections warrants further investigations on its mechanisms of action.