A promoting effect of thyroid hormones has been established on the maturation of central and peripheral nervous systems. However, effects on autonomic nerves have never been experimentally investigated. To assess the effect of a local treatment combining silicone guides and local administration of Triiodothyronine (T3) on the erectile function and the histological neuroregeneration of crushed cavernous nerves (CNs) in rats. Forty-five rats were divided into five equal groups: SHAM surgery, guide without crush, crush, crush+guide, crush+guide+T3. All surgical procedures were bilateral. CNs were crushed with microvascular bulldog clamp of 100g/cm2. A silicone guide was placed around the nerves. The guides were filled with T3 neuroregenerative solution. Erectile function was assessed 10 weeks post-operatively. Intra-cavernous pressure (ICP) and mean arterial pressure (MAP) were monitored during electrical stimulation of CNs at various frequencies. The main outcome was hardness of erection defined as ΔICP/MAP. Fluorescent immunohistochemical analysis of CNs was performed to assess regeneration of nerves morphologically. Electrophysiological data showed increased recovery of erectile function in the group with guide+T3 neuroregenerative solution compared with the empty guide. Immunohistochemical analysis of cavernous nerves demonstrated in morphology that regenerated axons were straighter in nerves with guide and more regular if guides had been filled with T3. The use of guides prevented axonal sprouting, facilitated functional neuroregeneration and enabled a local delivery of thyroid hormones. Triiodothyronine improved neuroregeneration and recovery of erectile function after a nerve-sparing–like injury in a rat model. Bessede T, Alsaid B, Ferretti L, Pierre M, Bernabé J, Giuliano F, Karam I, Benoît G, and Droupy S. Effect of a local delivery of triiodothyronine (T3) within neuroregenerative guide on recovery of erectile function in a rat-model of cavernous nerve injury.