Interferon-γ (IFN-γ) is believed to contribute to immune-mediated demyelinating disorders by targeting the myelin-producing oligodendrocyte, a cell known to be highly sensitive to the disruption of protein synthesis and to the perturbation of the secretory pathway. We found that apoptosis induced by IFN-γ in cultured rat oligodendrocytes was associated with endoplasmic reticulum (ER) stress. ER stress also accompanied oligodendrocyte apoptosis and hypomyelination in transgenic mice that inappropriately expressed IFN-γ in the central nervous system (CNS). Compared with a wild-type genetic background, the enforced expression of IFN-γ in mice that were heterozygous for a loss of function mutation in pancreatic ER kinase (PERK) dramatically reduced animal survival, promoted CNS hypomyelination, and enhanced oligodendrocyte loss. PERK encodes an ER stress-inducible kinase that phosphorylates eukaryotic translation initiation factor 2α and specifically maintains client protein homeostasis in the stressed ER. Therefore, the hypersensitivity of PERK+/- mice to IFN-γ implicates ER stress in demyelinating disorders that are induced by CNS inflammation.