A study of the comparative survival of islet xenografts using a combination of treatment modalities was carried out in the spontaneously diabetic BB/Wor rat. Islets were isolated from hamster donors, and after 4 to 6 days of incubation the cells were injected either into the immunologically privileged abdominal testis or into the nonimmunologically favored renal subcapsular space. Postoperatively the rats were given cyclosporine at two different dose schedules. The results showed that islets injected into the abdominal testis of nonimmunosuppressed rats caused the induction of normoglycemia with a mean duration of 8.3 +/- 1.3 days. A significant prolongation of normoglycemia to a mean of 36.1 +/- 4.5 days occurred in rats that were given abdominal, intratesticular islet xenografts and cyclosporine for 30 days. The longest average survival in excess of a mean of 90.1 +/- 6.5 days was achieved in rats that were given abdominal, intratesticular islet xenografts and cyclosporine continuously, every other day. All of the grafted rats reverted to diabetes upon the cessation of cyclosporine. A similar cyclosporine regimen failed to prolong islet xenograft survival for longer than a mean of 9.0 +/- 2.2 days in rats that were given islet xenografts injected into the renal subcapsular space. Extended survival of abdominal, intratesticular islet xenografts corresponded with trough plasma and testis cyclosporine levels of 457 +/- 46 ng/mL and 643 +/- 45 ng/g, of wet weight, respectively. It is concluded that islet xenografts are protected against immune destruction in the BB/Wor rat with type 1 diabetes only as long as the cells are injected into an immunologically privileged site and the host is continuously immunosuppressed with cyclosporine.