Introduction: Melatonin, the secretory product of the pineal gland, has potent antioxidant properties. The aim of this study was to compare the effects of low-dose (10 mg/kg) vs high-dose (50 mg/kg) melatonin on early lipid peroxidation levels and ultrastructural changes in experimental blunt sciatic nerve injury (SNI). We believe this to be the first study to assess the dose-dependent neuroprotective effects of melatonin after a blunt peripheral nerve injury. Materials and methods: Rats were randomly allocated into 5 groups of 10 animals each. The SNI only rats underwent a nerve injury procedure. The SNI plus vehicle group received SNI and intraperitoneal injection of vehicle (diluted ethanol) as a placebo. The SNI plus low-dose or high-dose melatonin groups received intraperitoneal melatonin at doses of 10 mg/kg or 50 mg/kg, respectively. Controls had no operation, melatonin or vehicle injection. SNI was induced by clamping the sciatic nerve at the upper border of the quadratus femoris for 2 min. Results: Sciatic nerve samples were harvested 6 h after nerve injury and processed for biochemical and ultrastructural analysis. Trauma increased the lipid peroxidation of the sciatic nerve by 3.6-fold (153.85±18.73 in SNI only vs 41.73±2.23 in control rats, P±0.01). Low (P=0.02) and high (P<0.01) doses of melatonin attenuated the nerve lipid peroxidation by 25% and 57.25%, respectively (65.76±2.47 in high-dose vs 115.08±7.03 in low-dose melatonin groups). Discussion: Although low-dose melatonin reduced trauma-induced myelin breakdown and axonal changes in the sciatic nerve, high-dose melatonin almost entirely neutralized any ultrastructural changes. Conclusion: Our results suggest that melatonin, especially at a dose of 50 mg/kg, has a potent neuroprotective effect and can preserve peripheral neural fibers from lipid peroxidative damage after blunt trauma. With further investigations, we hope that these data may prove useful to clinicians who treat patients with nerve injuries. © Springer-Verlag 2007.