The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain's stress axis, and its structure and function are particularly vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. We tested whether chronic social defeat produces structural alterations in the mPFC in mice. We first performed a microarray analysis of mPFC gene expression changes induced by defeat, and biological pathway analysis revealed a dominant pattern of down-regulation of myelin-associated genes. Indeed, 69% of the most significantly down-regulated genes were myelin-related. The down regulation was confirmed by in situ hybridization histochemistry for two strongly down-regulated genes, myelin oligodendrocyte glycoprotein (Mog) and ermin (Ermn), and by immunohistochemistry for myelin basic protein. To test for stress-induced changes in myelin integrity, aurophosphate (Black Gold) myelin staining was performed on mPFC sections. Quantitative stereologic analysis showed reduced myelinated fiber length and density. Behavioral analysis confirmed that the 14-day social defeat sessions resulted in induction of depressive-like states measured in social interaction and light/dark tests. The combined data suggest that chronic social defeat induces molecular changes that reduce myelination of the prefrontal cortex, which may be an underlying basis for stress-induced depressive states.