Objective: Adenoviral (Ad.) delivery of hepatocyte growth factor (HGF) to rodent islets improves islet graft survival and function, markedly reducing the number of islets required to achieve glucose control. Here, we asked whether these prior observations in rodent models extend to non-human primate (NHP) islets. Methods: NHP islets were transduced with murine (Ad.mHGF) or human (Ad.hHGF) Ad.HGF at low moi, and studied in vitro. To study the function of Ad.HGF-transduced NHP islets in vivo, a renal subcapsular marginal mass islet transplant model was developed in streptozotocin-induced diabetic NOD-SCID mice. Results: Baseline glucose values were 454.7+/-11.3 mg/dl (n=7). Transplant of 500 NHP islet equivalents (IE) had only a marginal effect on blood glucose (BG) (369.1+/-9.7 mg/dl, n=5). In striking contrast, 500 NHP IE transduced with Ad.mHGF promptly and continuously corrected the BG (142.0+/-6.2 mg/dl, n=7) for the six week duration of the experiment. Unilateral nephrectomy resulted in an immediate return of glucose to baseline diabetic levels. Interestingly, adenoviral DNA, as well as mHGF mRNA-derived from the adenovirus, were present for 42 days post-transplantation. Surprisingly, transplant of 500 IE with Ad.humanHGF, as compared to Ad.murineHGF, resulted in only marginal correction of BG, suggesting that hHGF is less efficient than mHGF in this system. Conclusions: These studies demonstrate that mHGF markedly improves islet transplant outcomes in the highest preclinical species examined to date. HGF has promise as an agent that can improve islet mass and function in transplant models, and likely in other models of Types 1 and 2 diabetes.