Peripheral nerve trauma remains one of the commonest conditions treated by plastic surgeons, yet despite major advances in microsurgical technique the clinical outcome remains poor in the majority of cases. To a large extent this reflects failure of the purely surgical approach to adequately address many of the neurobiological hurdles to optimal regeneration, amongst the most significant of which are the death of ~40% of sensory neurons, and the slow rate of regeneration of those that survive. Neuronal death is predominantly due to neurotrophic withdrawal, and involves mitochondrial dysfunction in the effector pathway; regeneration is trophin dependent, and requires increased aerobic glycolytic capacity. Acetyl-L-carnitine (ALCAR) is a physiological peptide with key roles in facilitating mitochondrial high-energy substrate oxidative metabolism. ALCAR increases neuronal binding of nerve growth factor and enhances bioenergetic capacity. It may therefore be neuroprotective, and enhance regeneration. Material & Methods After unilateral sciatic nerve transection in the rat, neuronal loss in the L4&5 dorsal root ganglia was quantified using the optical disector technique. The effect of systemic treatment with various doses of ALCAR was determined. The effect of ALCAR upon the myelin thickness of regenerating axons and target organ reinnervation was subsequently examined in a model of immediate nerve repair. Results Two weeks after axotomy neuronal loss was 21% in controls. At 50mg/kg/day ALCAR virtually eliminated neuronal death(2% neuronal loss, p=0.006). It was only marginally less effective at 10mg/kg/day, and a dose response was clearly evident at lower doses: 5mg/kg/day, 12% loss; 1mg/kg/day, 19% loss; 0.5mg/kg/day 23% loss. Neuroprotection persisted 2 month after axotomy (no treatment 35% loss; 50mg/kg/day ALCAR -4% loss, p<0.001). ALCAR treatment (50mg/kg/day) increased the myelin thickness of the regenerating axons(p<0.001) and the percentage area of immunostaining for nerve fibres within the footpad skin (211% increase, P<0.001),compared to untreated controls. Conclusion Systemic ALCAR treatment therefore virtually eliminates primary sensory neuronal death after peripheral neurometsis, and dramatically enhances target organ reinnervation. ALCAR therefore has the potential to address the major neurobiological hurdles to sensory restitution, and is proposed for the neoadjuvant pharmacotherapy of peripheral nerve trauma.