Ethanol (ETH) delays myelination in the sciatic nerve of rat following fetal exposure. It has been suggested that melatonin (MLT), a naturally occurring indole, may be a potential protective agent for ETH toxicity, possibly due to its protective effects against free radical damage in experimental models. However, the precise mechanism of MLT protection in the development of the rat sciatic nerves and their myelination is unclear. In this study, the effect of ETH, MLT and ETH+MLT on the myelin thickness, axon number and axonal area of rat sciatic nerve were investigated. Pregnant rats were injected with either 25% ETH (dosage 2g/kg body weight), 25% ETH plus MLT (dosage 2g/kg and 10 mg/kg, respectively), MLT (dosage 10 mg/kg) or physiological saline (dosage 1 ml/kg) at 7, 15 and 20 days post-conception (first, second and third trimesters, respectively). At postnatal day 14, sciatic nerves of offspring were dissected out and processed for stereological analyses. Our results demonstrated that the myelin thickness was increased by exogenous MLT, and decreased by acute ETH, during first and second trimesters. It was found that MLT was protective to developing myelin thickness following fetal exposure during the first trimester, whereas it was toxic to myelin thickness during the third trimester. The presented study is the frst stereological study indicating that exogenous MLT has a toxic efect on the myelin thickness of rat sciatic nerves during the third trimester. Based on our findings, we suggested that exogenous MLT, given during the third trimester as an antioxidant agent, as well as acute ETH, given in the first and second trimesters, may alter the normal development of sciatic nerve myelination. © 2009 OMU All rights reserved.