Sufficient numbers of pancreatic islets transplanted into the splenic pulp of streptozotocin-induced diabetic rats can result in complete reversal of hyperglycemia, glycosuria, and polyuria while promoting weight gain. These changes are constant for at least 3 months. Animals transplanted in this way, however, fail to exhibit a normal biphasic insulin response during an intravenous glucose tolerance test. This lack of biphasic response is in marked contrast to that observed in portal-vein--transplanted animals. Basal serum insulin in intrasplenic-transplanted animals is twice that observed in normal animals and portal-vein--transplanted animals which have received the same number of islet isografts. Direct injection of islets into the splenic pulp does not insure that subsequently all islets will remain in the splenic pulp, and, in fact, subsequent splenectomy suggests that in some cases a majority of transplanted tissue lodges in other organs--most likely, the liver.