We investigated the effect of intestinal ischemia, with and without reperfusion, in transgenic mice overexpressing the human superoxide dismutase(SOD) gene. Ischemia was induced by occluding the superior mesenteric artery in 2-4 month old (young) and 8 month old (adult) transgenic mice and in age-matched nontransgenic controls. In young animals, 60 min of ischemia without reperfusion was associated with a 55% (12/22) mortality in nontransgenic mice and 60% (6/10) mortality in transgenic mice. There were no deaths after 60 min of ischemia in adult, nontransgenic or transgenic mice. Fifty percent (5/10) of young nontransgenic mice died during the 4 hr reperfusion period, whereas no deaths were observed in transgenic mice in the same age group. All adult nontransgenic mice (4/4) died during the reperfusion period whereas all the transgenic mice in the same age group survived. In another experiment, the nontransgenic and transgenic mice survived 45 min ischemia followed by 4 hr reperfusion. After reperfusion, the young as well as adult nontransgenic mice exhibited a significant increase in lung myeloperoxidase activity whereas transgenic mice did not show this increase. These results indicate that older mice are able to tolerate a longer duration of intestinal ischemia than young animals. The overexpression of SOD in transgenic mice did not offer protection against mortality induced by ischemia without reperfusion. However, overexpression of SOD in transgenic mice provided protection against mortality induced by reperfusion injury. Protection appears to be due to the elimination of free radicals by SOD and due to decreased neutrophil sequestration in the lungs.