The development of strategies that will allow permanent survival of islet allografts without continuous host immunosuppression continues to be the most important goal in the field of pancreatic islet cell transplantation. In our study, we demonstrated that intrathymic inoculation of allogeneic spleen cell membrane antigens with a single dose of anti-lymphocyte serum induces an unresponsive state that permits survival of a subsequent pancreatic islet allograft to an extrathymic site (renal subcapsular space). This effect is donor specific and cannot be reproduced by the intravenous injection of spleen cell membrane antigens. Our results offer a potential approach for establishing donor-specific allograft acceptance in adult recipients.