BACKGROUND: The sciatic nerve is a peripheral nerve and is more vulnerable to compression with subsequent short- or long-term neuronal dysfunction. The current study was designed to elucidate the possible ameliorative effect of L-carnitine and sildenafil (SIL) on sciatic nerve crush injury. We sought to determine the effects of L-carnitine, a neuroprotective and a neuro-modulatory agent, and SIL citrate, a selective peripheral phosphodiesterases inhibitor, on modulating neuro-degenerative changes due to sciatic nerve compression. MATERIALS AND METHODS: The comparative effect of L-carnitine (at an oral dose of 20 mg/kg/day) or SIL citrate (20 mg/kg/day orally) administration for 21 days was studied in a rat model of sciatic nerve compression. Sciatic nerve sections were subjected to biochemical, histological, ultrastructure, and immunohistochemical studies to observe the effects of these treatments on neurofilament protein. RESULTS: The sciatic nerve crush injury group (group II) showed a significant decrease in tissue catalase (CAT), superoxide dismutase (SOD) and increase in malondialdehyde (MDA) as compared to control group (p < 0.01). Histological changes in the form of degenerated and vacuolated axoplasm with areas of nerve fibre loss and pyknotic nuclei were reported. The blood vessels were dilated, congested with areas of haemorrhage and mononuclear cell infiltration. Histo-morphometrically, a statistically significant reduction in the nerve fibres' number, mean axon cross-sectional area, myelin sheath thickness and a significant increase in collagen fibres' percentage (p < 0.05) as compared to control group. Immunohistochemically, neurofilament protein was significantly downregulated as proved by a significant reduction in mean area per cent of neurofilament expression. L-carnitine ameliorated the studied parameters through its neuroprotective effect while SIL, a selective peripheral phosphodiesterases (PDE-5) inhibitor, improved crush injury parameters but with less extent than L-carnitine. CONCLUSIONS: These findings indicate the valuable effects of L-carnitine administration compared to that of SIL citrate in alleviating the serious debilitating effects of sciatic nerve crush injury. Our results provide a new insight into the scope of neuroprotective and neuro-regenerative effects of L-carnitine in a sciatic nerve compression model.