Proteolytic enzyme inhibitors have been reported to decrease morbidity and mortality from certain types of experimental pancreatitis, although recent randomized trials have been unable to demonstrate that they are of benefit in the treatment of clinical acute pancreatitis. We have evaluated the effect of two proteolytic enzyme inhibitors (trasylol and chlorophyll-a) on experimental acute pancreatitis induced in mice by the feeding of a choline-deficient ethionine-enriched diet. The mortality rate and the biochemical and morphological severity of pancreatitis were not altered by either trasylol or chlorophyll-a administration. Thus, in this respect, diet-induced pancreatitis appears to resemble clinical acute pancreatitis. The reasons for the lack of effectiveness of proteolytic enzyme inhibitors in the treatment of both forms of pancreatitis are discussed.