The glucocorticoid dexamethasone (Dex) is widely used in preterm infants for the prevention of chronic lung disease. However, major concern has arisen about the long-term sequelae of this therapy. Here we report that neonatal treatment with dexamethasone significantly shortens the lifespan by 25% of male rats (28.6 +/- 1.1 to 21.3 +/- 0.8 mo) and by 18% of female rats (26.9 +/- 1.8 to 22.0 +/- 0.7 mo). Histopathological examination indicated end-stage cardiac and renal failure as the cause of premature death. Furthermore, Dex-treated rats showed symptoms of hypertension at young adult age, which worsened with increasing age. Thus, a brief period of glucocorticoid treatment during early life results in untimely death presumably due to cardiovascular and renal disease later in life. These serious, adverse long-term consequences call for prudence with glucocorticoid treatment of human preterm infants and careful follow-up of young adults with a history of neonatal glucocorticoid treatment.