Central pontine myelinolysis (CPM) is a rare but serious demyelinative disease that is associated with rapid correction of chronic hyponatremia. Disruption of the blood-brain barrier (BBB) following a rapid increase in serum sodium concentration is considered to play a critical role in the pathogenesis of osmotic demyelination. We investigated the protective effect of dexamethasone (DEX) on osmotic demyelination in rats. After rapid correction of chronic hyponatremia, rats displayed serious neurologic impairments and demyelinative lesions were observed in various brain regions. Conversely, DEX-treated rats exhibited minimal neurologic impairments and demyelinative lesions were rarely seen in the brain. A marked extravasation of endogenous immunoglobulin G and Evans blue dye were observed in the brains of rats that did not receive DEX, indicating disruption of the BBB, but this was not observed in DEX-treated rats. These results indicate that DEX is effective in preventing osmotic demyelination by inhibiting BBB disruption, and suggest that DEX might be useful for the prevention of CPM in clinical practice.