We have previously reported the preparation of vascularized islet-kidneys (IKs) by transplantation of islets under the autologous kidney capsule. Here, we compare the efficacy of transplanting vascularized versus nonvascularized islets into diabetic allogeneic swine recipients. In the vascularized islet transplantation (5,000 islet equivalents [IE]/kg), recipients received minor-mismatched (n = 4) or fully-mismatched (n = 2) IKs after pancreatectomy, with a 12-day course of cyclosporine A (CyA) or FK506, respectively. For the nonvascularized islet transplantation (7,000 IE/kg), three recipients received minor-mismatched islets alone and two recipients received minor-mismatched donor islets placed in a donor kidney on the day of transplantation. All recipients of nonvascularized islets were treated with a 12-day course of CyA. With vascularized islet transplantation, pancreatectomized recipients were markedly hyperglycemic pretransplant (fasting blood glucose >300 mg/dl). After composite IK transplantation, all recipients developed and maintained normoglycemia (<120 mg/dl) and stable renal function indefinitely (>3 months), and insulin therapy was not required. Major histocompatibility complex-mismatched recipients demonstrated in vitro donor-specific unresponsiveness. In contrast, recipients of nonvascularized islets remained hyperglycemic. In conclusion, IK allografts cured surgically induced diabetes across allogeneic barriers, whereas nonvascularized islet transplants did not. These data indicate that prevascularization of islet allografts is crucial for their subsequent engraftment and that composite IKs may provide a strategy for successful islet transplantation.