Previous work showed that the susceptibility of oligodendroglial progenitors to oxidative stress is related to their low reduced-glutathione (GSH) and high iron contents. This suggests that these cells have a poor ability to scavenge peroxides. All peroxides are scavenged by glutathione peroxidase. Glutathione peroxidase activity requires GSH as an electron donor resulting in the formation of oxidized-glutathione. Cellular GSH content is dependent upon synthesis as well as reduction of oxidized-glutathione. The objectives of the present study were to compare several parameters important in the ability to scavenge peroxides between astrocytes and oligodendroglia. Three stages of oligodendroglial differentiation were examined: the proliferative oligodendrocyte progenitor, the proliferative oligodendroblast, and the post-mitotic oligodendrocyte. We demonstrate that oligodendroglia at all stages of differentiation have less than one-half the content of GSH compared to astrocytes. This low level of GSH is due in part to a lower rate of GSH synthesis in oligodendroglia compared to astrocytes and in part to their having only one-half of the glutathione reductase activity of astrocytes. Glutathione peroxidase activity of oligodendroglia is less than 15% of that found in astrocytes. The low GSH and concomitant low glutathione peroxidase activity would tend to maintain peroxides at levels that are dangerously high if iron is released from iron stores. Oligodendroglia have high iron stores, and thus these findings emphasize how vulnerable the oligodendroglial lineage is to perturbations that result in oxidative stress.