It is well known that chronic ethanol treatment affects the synthesis of RNA and protein in the brain and the maintenance and function of nervous system. The changes in myelination-related genes are most prominent in human alcoholics. Previously, our cDNA microarray study showed altered Proteolipid protein (PLP), a major protein of central myelin. The present study aimed to gain more understanding of the expression of PLP after chronic ethanol treatment. Male Sprague-Dawley rats were daily treated with ethanol (15% in saline, 3 g/kg, i.p.) or saline for 14 days. Messenger RNAs from hippocampus of each group were subjected to cDNA expression array hybridization to determine the differential gene expressions. Among many ethanol responsive genes, PLP was negatively regulated by ethanol treatment, which is one of the most abundant proteins in the CNS and has an important role in the stabilization of myelin sheath. Using northern blot and immunohistochemical analysis, we showed the change in expression level of PLP mRNA and protein after ethanol treatment. PLP mRNA and protein were decreased in hippocampus of rat with chronic ethanol exposure, suggesting that ethanol may affect the stabilization of myelin sheath through the modulation of PLP expression and induce the pathophysiology of alcoholic brain.