Peripheral nerve injury is a common and devastating complication after trauma and can cause irreversible impairment or even complete functional loss of the affected limb. While surgical coaptation of peripheral nerves results in some axonal regeneration and functional recovery, the clinical outcome in long distance nerve defects especially after use of artificial nerve grafts is still disappointing driving the search for alternatives to optimize functional recovery. Purpose: In our study, we investigated the capacity of spide silk fibers to guide axonal growth in long nerve defects in adult sheep. Material and Methods: Nerve graft constructs consisted of decellularized allogeneic vein grafts filled with longitudinally oriented spider silk fibers as a guiding material to bridge a 6.0 cm tibial nerve defect . We compared allogenic nerve constructs to autologous nerve grafts in groups of 8 animals each . After 5 months nerve regeneration was evaluated clinically and histologically for the following parameters: functional integration , axonal regeneration, remyelination and formation of nodes of Ranvier. All animals were functionally tested using gait analysis and pin prick test for sensitivity. Morphological studies involved immunostaining and EM. Immunostaining for Na+ channel (NaV 1.6) was used to define nodes of Ranvier on regenerated axons in combination with myelin basic protein (MBP) and neurofilament. Anti-S100β was used to identify Schwann cells. Results: Sheep did not differ in functional recovery clinically among the groups. All constructs survived and integrated into the repaired nerves. Regenerated nerves stained for anti-S100 indicating migration of Schwann cells into the construct and neurofilament demonstrating axonal regrowth throughout the 6.0 cm nerve defect were found in both goups. Also positive staining for MBP revealed remyelination of regenerated nerve fibers in the constructs. Nodes of Ranvier between Schwann cells in the construct were observed and identified by intense sodium channel (NaV 1.6) staining on the regenerated axons. Conclusions: This study demonstrates that spider silk based nerve grafts enable Schwann cell migration, axonal regrowth and remyelination in a long-distance peripheral nerve gap model. Results are comparable to autologous nerves. This improvement in nerve regeneration could have significant clinical implications for reconstructive nerve surgery.