We have investigated the influence of glycemic control on the number of transplanted neonatal islets needed to cure streptozotocin (STZ)-diabetic rats. Intrasplenic transplantation of 1000 neonatal islets to a group of STZ-diabetic rats with poor glycemic control cured only 30% of the rats. In a second group, insulin at doses of 10-15 U/day given for 5 days after transplantation improved the cure rate to 72%. Normalization of blood glucose by a previous transplant to the kidney capsule produced cure in 100% of the rats. The above results were obtained despite the fact that isolated adult islets, when compared with neonatal islets, were larger, contained more protein and DNA--and, in response to glucose stimulation, released more insulin than neonatal islets. These experiments show that neonatal islets are an excellent source of endocrine replacement tissue when transplanted intrasplenically, and that the number of islets needed to cure experimental diabetes is significantly reduced by normalization of the metabolic milieu in the recipient.