The role of the thymus in the ongoing acquisition of tolerance to self antigens has made it an attractive site for islet transplantation. Several studies have reported survival of rodent islet allografts in the thymus without requiring the long-term use of immunosuppressive agents; however, the degree of glucose homeostasis in the intrathymic islet transplant recipients has not been examined. We transplanted 500, 1000, or 2000 syngeneic islets into the thymus of streptozotocin-induced diabetic Wistar-Furth rats, and compared the metabolic response of these recipients with animals receiving 2000 syngeneic islets under the kidney capsule. Three of four recipients which received 2000 islets under the kidney capsule achieved normoglycemia (< or =8.4 mmol/L) within 1 wk and all animals became normoglycemic within 2 wk posttransplantation. In contrast, intrathymic implantation of 2000 islets induced normoglycemia in only one of six recipients during the same time interval, and when this number was reduced to 1000 or 500 islets, none of the recipients (n = 6) normalized within 1 wk posttransplantation. Animals that received an intrathymic transplant were glucose intolerant compared to normal controls and animals with subcapsular islet transplant. Removal of the graft-bearing organs resulted in hyperglycemia in all cases, and examination of the grafts revealed the presence of numerous well-granulated insulin-containing cells in both sites. The cellular insulin content of the subcapsular grafts (67.4 +/- 12.1 microg; n = 4) was significantly higher (p < or =0.05) than what was extracted from intrathymic grafts (9.5 +/- 1.2 microg from 1000 islets; n = 3 and 20.0 +/- 4.6 microg from 2000 islets; n = 3). We conclude that 2000 syngeneic islets implanted either in the thymus or beneath the kidney capsule can normalize hyperglycemia in streptozotocin-diabetic rats; however, normal glucose tolerance was not established in intrathymic islet recipients, suggesting that a higher number of islets may be necessary to achieve normal glucose homeostasis.