The BB rat spontaneously develops autoimmune diabetes. Feeding these animals a hydrolyzed casein diet significantly reduces the incidence of this disease, suggesting that a dietary antigen is involved in the pathogenesis of this disease. In other syndromes associated with luminal antigens, including celiac and Crohn's disease, increased intestinal permeability has been suggested to play an etiological role. Therefore, the objective of this study was to evaluate whether increased permeability was also present in BB rats before disease development. By measuring gastrointestinal permeability, in animals on a regular or hydrolyzed casein diet, we were able to demonstrate that increased gastric and small intestinal permeability appeared before the development of both insulitis and clinical diabetes. Although hydrolysis of dietary protein significantly reduced the incidence of diabetes, it did not alter the small intestinal permeability abnormality, suggesting that this is an early event. Increased permeability appears to have an early role in the genesis of several immunological diseases and may represent a common event in these diseases.