Aim: Neuroprotective effects of ebselen against free radical damage have been studied extensively. Toluene generates reactive oxygen species (ROS) and the toxic effects relating to these reactants. The aim of this study was designed to investigate the effects of chronic toluene inhalation in high concentration on lipid peroxidation, antioxidant enzyme activities and ultrastructural changes in the sciatic nerves of rats. Methods: We also examined the protective effects of ebselen against toluen exposure. Male Wistar albino rats (150-250 g) were divided in three experimental groups: the control, toluene and toluene+ebselen treated group (n=10 for each). Toluene treatment was performed by inhalation of 3000 ppm toluene, in a 8 hr/day and 6 day/week order for 16 weeks. Control group received 1ml serum physiologic and ebselen was given i.p. (10 mg/kg) to toluene+ebselen treated group just after toluene exposure per day. Blood and tissue samples were obtained for biochemical and histopathological investigation. The blood and sciatic nerves were assayed for toluene by gas chromatography. Results: Toluene significantly increased blood and tissue malondialdehyde (MDA), and decreased tissue superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), but not tissue catalase (CAT) levels when compared with controls. Ebselen administration prevented to increase of blood and tissue MDA and decrease to SOD and GSH-Px levels induced by toluene inhalation. Electron micrographs of sciatic nerve in the toluene group shows myelin destructions with onion-bulb and bubble form protrusion on the myelin sheath and axolemma border of myelinated axons. Furthermore, ebselen salvaged the nerve fibers from toluene exposure. Conclusion: Ebselen treatment may provide neuroprotection against toluene neurotoxicity by directly scavenging ROS and by indirectly augmenting their antioxidant capacity.