Syngeneic transplantation of 200 mouse islets under the kidney capsule usually fails to cure streptozocin-induced diabetes. We hypothesized that this number of islets, if engrafted in a normoglycemic environment, could expand their mass and improve their function to restore normoglycemia. Therefore, 200 freshly isolated mouse islets were transplanted under the capsule of each kidney of diabetic mice. Two weeks after transplantation, the recipients were normoglycemic, and one of the two grafts was removed. Removal of the graft was followed by transient hyperglycemia. At day 14 after graft removal, the β-cell mass and insulin content of the remaining graft had increased 2.3- and 2.1-fold, respectively. At day 3 after graft removal, the replication rate of β-cells increased threefold, and the mean individual β-cell crosssectional area, an indicator of cell size, was also increased. Perfusion of the kidney bearing the remaining graft showed biphasic insulin responses to high glucose and arginine 14 days after one graft removal. These data indicate that maintaining a period of near-normoglycemia after islet transplantation enhances the performance of an islet graft that would otherwise be expected to fail.