ABSTRACT Clinical trials have shown that intrahepatic islet transplant in patients with brittle type 1 diabetes (T1D) improves their quality-of-life significantly. This is achieved through improvement in glycemic control, restoration of severe hypoglycemia awareness, and prevention of diabetes-associated morbidities. However, it has also become evident that the longevity of the intrahepatic islet graft is limited by liver-specific complications, such as IBMIR (Instant Blood Mediated Inflammatory Reaction), hypoxia, and drug toxicity. Consequently, several new sites for islet transplant are being evaluated in clinical trials including the anterior chamber of the eye (ACE; see ClinicalTrials.gov/NCT02846571). Our extensive preclinical studies have shown that the ACE is a viable site for islet transplantation with several technical advantages that can be exploited to promote graft longevity. We recently demonstrated in the baboon long-term survival of islet allografts in the ACE long after stopping immunosuppression. Building on our prior work, the primary objective of the current project is, therefore, to evaluate whether complete independence from exogenous insulin therapy can be achieved following intraocular islet transplant alone or with a follow-up second transplant in the periphery in same diabetic recipient baboons that have been tolerized through initial islet transplant in the ACE. The successful implementation of this proposed research will further support the clinical transition/application of intraocular islet transplant as an effective and sustainable therapy of T1D.