Several lines of evidence suggest that peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists may control brain inflammation and, therefore, may be useful for the treatment of human CNS inflammatory conditions. The PPAR-gamma agonists delay the onset and ameliorate clinical manifestations in animal demyelinating disease models, in which the beneficial effects are thought to be mainly related to anti-inflammatory effects on peripheral and brain immune cells. Direct effects on neurons, oligodendrocytes, and other CNS resident cells cannot be excluded, however. To analyze potential direct actions of PPAR-gamma agonists on oligodendrocytes, we investigated the effects of both natural (15-deoxy Delta prostaglandin J2) and synthetic (pioglitazone) PPAR-gamma agonists in primary cultures of rat oligodendrocyte progenitor cells. The PPAR-gamma agonists promoted oligodendrocyte progenitor cell differentiation and enhanced their antioxidant defenses by increasing levels of catalase and copper-zinc superoxide dismutase while maintaining the overall homeostasis of the glutathione system. Protective effects were abolished in the presence of the specific PPAR-gamma antagonist GW9662, indicating that they are specifically dependent on PPAR-gamma. These observations suggest that in addition to their known anti-inflammatory effects, PPAR-gamma agonists may protect oligodendrocyte progenitor cells by preserving their integrity and favoring their differentiation into myelin-forming cells. Thus, PPAR-gamma may promote recovery from demyelination by direct effects on oligodendrocytes.