Background. Significant functional decrease and sclerosis of the pancreas graft in late delays cannot only be related to chronic rejection. Any transplantation leads to graft denervation, which may be an important cause of dysfunction. Studies concerning graft reinnervation were controversial. Purpose of the Study The purpose of this study was to investigate the feasibility and pertinence of a surgically directed reinnervation (SDR) of denervated/neuro- reflex isolated (NRI) or autotransplanted (aTx) pancreas. Basic Procedures Anatomy of the nerves penetrating into the pancreas was studied in humans, dogs, cats, and rats. Surgery and physiological investigations were performed in dogs, cats, and rats. Nervous conductivity between NRI, NRI+SDR pancreas, and brain was tested. Load tests with glucose, insulin, and adrenalin were performed; amylase and lipase were determined in fasted and not fasted animals to evaluate the influence of NRI and SDR on pancreatic function. Histology was provided. Observation delays were 6 months. Main Findings Anatomic feasibility of SDR in humans and animals was proved. Models of pancreatic tail NRI and surgical reconstitution of the interrupted nervous pathways (SDR) were elaborated in animals. The restoration of the pancreas-brain reflex axis after SDR was electro physiologically proved. As blood glucose curves after load test, exocrine amylase and lipase determination have shown that pancreas NRI or aTx leads to an exaggerated reaction to usual stimulations that may cause the observed graft functional exhaustion in late delays. SDR shortened the period of the graft neuro-reflex isolation, contributed to a quick normalization of its function, and prevented its late degradation. Conclusion. SDR was shown to be a simple surgical technique, easily performed after the graft surgical revascularization. Its functional and morphological efficiency was tested and proved. Thus, SDR may be recommended in human pancreas transplantation as pertinent. © 2014 by Elsevier Inc. All rights reserved.