Hyperplastic islets of Langerhans from 129/J db3J/db3J mice were used to test the efficacy of the cleared mammary fat pad as an ectopic transplantation site. Eight to 10 islets were inoculated into a cleared mammary fat pad of syngeneic 129/J or allogeneic BALB/cByJ female mice following diabetes induction using streptozotocin. Islets transplanted into syngeneic hosts reversed the weight loss and hyperglycemia characteristic of nontransplanted streptozotocin-diabetic mice. In contrast to the degenerate islets found in the host pancreas, the ectopic islets were filled with well-granulated beta cells and they incorporated 3H-thymidine. Islets transplanted into allogeneic BALB/cByJ diabetic hosts produced weight gain and remission of hyperglycemia in four of six recipients. Extirpation at the 9th week of the cleared fat pad containing the islet graft in one of the cured mice returned the animal to a hyperglycemic state within 1 week. Although some of the grafted islets in allogeneic hosts appeared to be completely intact at 8 weeks, others appeared to be undergoing rejection by the host. Nevertheless, the maintenance of viable and functional islets in the cleared fat pads in H-2-histoincompatible recipients for 8 weeks without immunosuppression of the host or prior culture of the islets makes this model attractive for further study as a potentially immunoprivileged site.