Oral administration of relevant autoantigens is being considered as a realistic approach for the prevention of several autoimmune diseases. In this study we administered, orally, to young female NOD/Ak mice (diabetes incidence, 40%) and NOD/LtJ mice (diabetes incidence, 70%) whole pancreatic extract on days 19, 20, 21, 22, 23, 26, and 27 and studied its effects on the development of diabetes until day 250. The cumulative incidence of diabetes in both the colonies after pancreatic extract treatment was compared with the incidence after oral administration of syngeneic liver extract or in untreated mice. In the NOD/Ak mice, the incidence of diabetes in the pancreatic extract group was significantly lower (6%; n = 34, p = 0.004) and was delayed compared with 33% in the liver group (n = 34) and 44% in the untreated group (n = 18). Significant protection from diabetes and a delay in its onset also were observed in the NOD/LtJ mice treated with pancreatic extract (16%; n = 19, p = 0.002) compared with those liver extract treated (72%; n = 18) and in untreated mice (60%; n = 22). Pancreatic histology at day 90 from all the study groups showed that the protection from diabetes in the pancreatic-extract group was not associated with reduced insulitis. We speculate that the marked disease protection observed in this study with orally administered pancreatic extract may be associated with the presence of immunoregulatory cells with a predominant Th2 cytokine bias. Our studies may have implications for the prevention of insulin-dependent diabetes mellitus (IDDM) in humans.