Barriers to the use of islet transplantation as a practical treatment for diabetes include the limited number of available donor pancreata. This project was designed to determine whether the size of the islet could influence the success rate of islet transplantations in rats. Islets from adult rats were divided into 2 groups containing small (diameter < 125 µm) or large islets (> 150 µm). An average pancreas yielded 3 times more small islets than large. Smaller islets were approximately 20% more viable, with large islets containing a scattered pattern of necrotic and apoptotic cells or central core cell death. Small islets in culture consumed twice as much oxygen as large islets when normalized for the same islet equivalents. In static incubation small islets released 3 times more insulin under basal conditions than large islets. During exposure to high glucose conditions, the small islets released 4 times more insulin than the same islet equivalencies of large islets, and 5 times more insulin was released by the small islets in response to glucose and depolarization with K⁺. Most importantly, the small islets were far superior to large islets when transplanted into diabetic animals. When marginal islet equivalencies were used for renal subcapsular transplantation, large islets failed to produce euglycemia in any recipient rats, while small islets were successful 80% of the time. The results indicate that small islets are superior to large islets in in vitro testing and for transplantation into the kidney capsule of diabetic rats.