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The changes in short circuit current (electrogenic Cl- secretion) of rat colon brought about by xanthine/xanthine oxidase in the Ussing chamber were inhibited by catalase and diethyldithiocarbamate, but not by superoxide dismutase. These results, the reproduction of the response with glucose/glucose oxidase and with exogenous H2O2, and the lack of effect of preincubation with deferoxamine or thiourea implicate H2O2, and not O2- or OH., as the important reactive oxygen metabolite altering intestinal electrolyte transport. 1 mM H2O2 stimulated colonic PGE2 and PGI2 production 8- and 15-fold, respectively, inhibited neutral NaCl absorption, and stimulated biphasic electrogenic Cl secretion with little effect on enterocyte lactic dehydrogenase release, epithelial conductance, or histology. Cl- secretion was reduced by cyclooxygenase inhibition. Also, the Cl- secretion, but not the increase in prostaglandin production, was reduced by enteric nervous system blockade with tetrodotoxin, hexamethonium, or atropine. Thus, H2O2 appears to alter electrolyte transport by releasing prostaglandins that activate the enteric nervous system. The change in short circuit current in response to Iloprost, but not PGE2, was blocked by tetrodotoxin. Therefore, PGI2 may be the mediator of the H2O2 response. H2O2 produced in nontoxic concentrations in the inflamed gut could have significant physiologic effects on intestinal water and electrolyte transport.