One hour of regional ischemia significantly increases the permeability of intestinal capillaries. The role of local humoral agents in the genesis of an increased capillary permeability in the ischemic bowel was assessed using specific antagonists to substances commonly believed to be involved in the pathogenesis of ischemic states. Capillary permeability estimates in autoperfused segments of cat ileum were derived from the relationship between lymph-to-plasma protein concentration ratio and lymph flow. Pretreatment of the ileal segments with either benadryl + cimetidine, indomethacin, or methylprednisolone did not significantly alter the permeability increase induced by regional ischemia. Pretreatment with superoxide dismutase (SOD), a superoxide radical scavenging enzyme, significantly attenuated the capillary permeability change induced by regional ischemia. Intravenous E. coli endotoxin administration in normotensive preparations increased intestinal capillary permeability; however, lethal doses of the endotoxin were required. The results of this study indicate that superoxide radicals are primarily responsible for the increased capillary permeability in the ischemic bowel.