The role of oxygen-derived free radicals in the pathogenesis of acute pancreatitis was studied by evaluating the effects of catalase, allopurinol, and dimethylsulfoxide on diet-induced acute hemorrhagic pancreatic necrosis in mice. The mortality rate and degree of hyperamylasemia associated with this model of pancreatitis were reduced by catalase but a similar result followed the administration of heat-denatured catalase, suggesting that the apparent protective effect of catalase was not the result of reductions in free radical levels. Neither allopurinol nor dimethylsulfoxide reduced mortality or degree of hyperamylasemia. The increased pancreatic content of amylase and the necrosis that characterize this model of pancreatitis were not altered by any of the agents tested. In contrast, both allopurinol and dimethylsulfoxide reduced peripancreatic edema formation, suggesting that edema, but not the other features that characterize this model of pancreatitis, may result from generation of oxygen-derived free radicals.