Biodegradable polyurethane-based (PU) nerve guides, instilled with or without ACTH4-9 analog (a melanocortin) were used for bridging an 8 mm gap in the rat sciatic nerve and were evaluated for function and histological appearance after 16 weeks of implantation. Autologous nerve grafts functioned as controls. The guides successfully enabled the sciatic nerve to regenerate across the 8 mm gap, thus effectively reestablishing the contact between the proximal and distal nerve ends. The mean conduction velocity, motor latency, and muscle action potentials of all the nerve guides did not diff er significantly from the autografts. The histological quality of the regeneration in the nerve guides was significantly better than in the autografts; in the nerve guides, a well-defined nerve cable of normal architecture had regenerated without extensive endoneural scarring as seen in the autografts. ACTH4-9 instilled in the nerve guides showed a slight, but significant, increase in the number of myelinated axons. It is concluded that biodegradable PU nerve guides result in similar functional recovery when compared with autografts, but their histological quality is significantly better. ACTH4-9 showed only slight, but significant, improved nerve growth promoting activity. Therefore biodegradable PU nerve guides with ACTH4-9 would appear to be promising alternatives to autografts for bridging nerve defects.