The effect of in vivo administration of exogenous tumor necrosis factor- α on the survival of rat islet xenografts in STZ-induced diabetic mice was examined. Daily subcutaneous injections of purified recombinant murine TNF- α (3 μg/day) for 7 days after transplantation of islets prolonged the survival of the xenografts (26.7 ± 4.9 days) compared with controls (11.2 ± 1.1 days). Extension of the treatment from 0 to 59 days after transplantation produced an even greater prolongation of graft survival (53.7 ± 8.5 days). After cessation of treatment, an accelerated rejection of the grafts occurred. A most interesting finding was that delaying initiation of treatment until 3 days after transplantation and continuing until 60 days produced a remarkable prolongation of xenograft survival (mean survival time >89.8 ± 17.5 days) with 2 recipients still normoglycemic at 124 days. Removal of the grafts at this time returned the 2 mice to a diabetic state. A second islet transplant from the same donor rat strain (Wistar-Furth) had an accelerated rejection, indicating that the long-term survival of the xenografts was not because of induction of tolerance. Delaying initiation of TNF treatment until 6 days after transplantation produced only a slight prolongation of survival (17.5 ± 1.2 days). Prolongation of islet xenograft survival also was obtained by continuous, subcutaneous delivery of TNF-α by a 7-day miniosmotic pump (3 μg/day). Lower daily doses of TNF-α (0.003, 0.3, and 1.0 μg) had no effect on graft survival. The findings indicate that daily subcutaneous injections of TNF-α will prevent rejection of rat islet xenografts, and if treatment is initiated early in the rejection process (3 days), then marked prolongation of survival continues even after cessation of treatment with TNF-α.