The effects on the pancreas of chronic (95 wk) dietary exposure to protease inhibitors from soy and potato were compared in rats and mice. Soy and potato trypsin inhibitor (TI) concentrates were prepared from defatted raw soy flour and potato juice, respectively, by selective precipitation and ultrafiltration. Animals were fed a diet in which casein supplied approximately 20% protein. Each concentrate (less than 1% of the diet) was added to provide 100 and 200 mg of trypsin inhibitor activity per 100 g of diet. In short-term (28 d) experiments in rats, both sources of TI decreased the apparent nutritional quality of casein and produced pancreatic hypertrophy consistent with a hormonally mediated feedback mechanism for pancreatic adaptation to diet that is interactive with the nutritional status of the animal. After long-term feeding (95 wk), soy and potato TI produced dose-related pancreatic pathology in rats consisting of nodular hyperplasia and acinar adenoma, which was typical of that associated with raw soy flour. Although mice responded similarly to rats to soy TI in short-term (28-d) feeding experiments, they were resistant to the formation of these lesions following long-term feeding. This considerable species variation in propensity to develop preneoplastic and neoplastic lesions of the pancreas is not predicted by the short-term hypertrophic and hyperplastic response of the pancreas to TI.