Extended survival of canine islet xenografts implanted in spontaneously diabetic BB/Wor rats has been achieved by islet encapsulation inside cylindrical chambers fabricated from permselective acrylic membranes. Intraperitoneal implantation of the encapsulated islets reversed the diabetic state of the 10 recipients within 24 h. Plasma glucose levels declined from a preimplantation level of 459 +/- 30 to 102 +/- 14 mg/dl during the first 10 days. All of the animals sustained these levels for at least 1 month, and 2 animals for at least 2 and 8 months, respectively. To confirm that glucose homeostasis resulted from the encapsulated islet grafts, the implants were removed from 2 rats 1 month postimplantation, whereas a third was removed at 2 months. Hyperglycemia was observed immediately in all 3 animals, with glucose levels rising from 100 +/- 3 to 510 +/- 43 mg/dl within 1 day. In contrast, diabetic control rats (n = 4) receiving nonencapsulated islets became hyperglycemic in less than 1 week. The iv glucose tolerance test K value (decline in glucose levels, percent per min) at 10 days was 2.3 +/- 0.4 compared with 0.6 +/- 0.1 (P less than 0.005) and 3.1 +/- 0.1 (P less than 0.02) for untreated diabetic (n = 4) and normal control (n = 4) groups. Histological analyses and electron microscopy of long term functioning grafts revealed well preserved islets, with hormone-producing alpha-, beta-, and delta-cells; the membranes were generally free of fibrosis and host cell adherence. These results demonstrate that permselective artificial membranes can protect discordant islet xenografts from both graft rejection and autoimmune destruction for more than 1 month in an animal model that is similar in several respects to human type I diabetes.