Prolonged survival of Islet- allo- and xenografts can be induced following implantation of the islets into the abdominal testis of diabetic rats. We previously showed that a factor released by Sertoli cells appears to be responsible for the protection of the intratesticular islet allo- and xenografts against rejection. The aim of this study was to examine whether an immunologically privileged site can be established in an organ site in vivo, other than the testis, such as the renal, subcapsular space, to make feasible the grafting of female recipients as well. A total of 36 male and 21 female, diabetic, PVG rats were divided into six different treatment groups: 1) Six male rats were grafted with islets from Sprague-Dawley (S-D) donor rats only. 2) Ten male rats were grafted with islets from (S-D) donors and were then given a short course of cyclosporine (CsA) posttransplantation. 3) Ten male rats were grafted with islets from (S-D) donors and with Sertoli cell-enriched fractions (SEF) from PVG donors but without CsA. 4) Ten male rats were grafted with a combination of islets from (S-D) and SEF from (PVG), donors, respectively, and CsA. 5) Ten female rats were given an identical combination of cells and CsA as depicted for group 5.6) Ten female rats were grafted with a combination of islets and SEF, both cell types from S-D donors, and CsA. The results showed that 70% to 100% of the grafted rats in groups 1, 2, and 3 remained hyperglycemic. Prolonged normoglycemia in excess of 100 days was induced in more than 75% of the grafted rats only in groups 4,5, and 6, or in those animals who were grafted with a combination of islets and SEF and who were given a short course of CsA as well. Electron microscopic examination of the grafted tissues showed the presence of intact beta cells and of cells with features characteristic of Sertoli cells. Our results suggest that 1) the protection of islet allografts in nonimmunologically privileged site can be achieved in male and female rats by means of the simultaneous transplantation of Sertoli cells. 2) Sertoli cells apparently maintain the capacity to secrete an immune inhibitor in organ sites other than the testis. We conclude that it is feasible to create an immunologically privileged site for the transplantation of isolated islets in male and female diabetic recipients without the need for sustained immunosuppression.