Osmotic demyelination unrelated to hyponatremia is rarely reported. We present a case of osmotic demyelination in a patient with hypernatremia in the absence of preceding hyponatremia and review previously reported cases of osmotic demyelination in nonhyponatremic patients. We conclude that a rapid increase in serum sodium concentration and plasma tonicity even in the absence of preceding hyponatremia may surpass the brain’s capacity for adaptation to hypertonicity and lead to osmotic demyelination in predisposed individuals.