It has been postulated that oxygen-derived free radicals are produced in significant quantities upon reperfusion of ischemic brain and could cause brain edema and cell death. This study was undertaken in an attempt to examine the effect of recombinant human superoxide dismutase, a scavenger of superoxide radicals, on survival outcome and brain edema in gerbils undergoing 1-hour bilateral carotid occlusion and reperfusion. Superoxide dismutase was continuously infused over either 1 or 3 h of reperfusion. Neither low dose (100,000 U/kg bolus followed by 100,000 U/kg/h continuous infusion) nor high dose (100,000 U/kg bolus followed by 800,000 U/kg/h) recombinant human superoxide dismutase had an effect upon water and sodium content of whole brain at 1 h of reperfusion following 1 h of ischemia, but high-dose treatment effectively reduced brain water content at 3 h of reperfusion. All gerbils receiving high-dose treatment survived the 3 h of reperfusion, while 4 of the 7 gerbils in the control group died between 2 and 3 h of reperfusion (p less than 0.05). From this study, we conclude that prophylactic administration of superoxide dismutase can reduce the delayed vasogenic edema developing at 3 h of reperfusion and afford significant cerebroprotection in these models of transient global ischemia.