OBJECTIVE: To describe the ability of nonhuman primate endocrine pancreata to reestablish endogenous insulin production after chemical beta-cell destruction. RESEARCH DESIGN AND METHODS: Eleven monkeys (Macaca fascicularis) were rendered diabetic with streptozotocin. Eight diabetic monkeys received intraportal porcine islet transplantation. RESULTS: Two monkeys transplanted after 75 days of type 1 diabetes showed recovery of endogenous C-peptide production a few weeks after transplantation, concomitant with graft failure. Histological analysis of the pancreas of these monkeys showed insulin-positive cells, single or in small aggregates, scattered in the pancreas and adjacent to ducts. Interestingly, numerous CK19(+) cells costained with proinsulin and PDX-1 antibodies. Furthermore, the peculiar double phenotype glucagon-positive/GLUT2(+) was observed. In these monkeys as well as in all others, the original islets showed no insulin staining. CONCLUSIONS: Our data provide evidence that, in nonhuman primates, the pancreas can reestablish endogenous insulin production after chemical beta-cell destruction. This seems to be a nongeneralizable event with only 2 out of 11 monkeys recovering beta-cell function. In these two monkeys, younger age and islet graft behavior might have played a role in triggering endogenous beta-cell recovery.