To determine the relative contribution of sudden death as a cause of late inpatient mortality in newborns after prolonged mechanical ventilation, we reviewed the charts of 348 patients who received ventilation assistance and who were admitted to the neonatal intensive care unit during a 26-month period. The overall mortality rate for these patients was 25%, with 88% (77/88) of these deaths occurring within 30 days of birth. Eleven infants died after more than 60 days of mechanical ventilation. Seven of these late deaths were sudden, unexpected in-hospital deaths. Sudden deaths occurred at a mean (uncorrected) age of 12 months (range, 4 to 27 months), during periods when infants appeared to be stable or clinically improving, were unrelated to recent respiratory exacerbations, and occurred despite prompt resuscitative efforts. Four infants still required mechanical ventilation, and 4 had tracheostomies at the time of death. All of the infants had chronic hypercarbia (greater than 50 mm Hg) and an elevated serum bicarbonate level (greater than 30 mmol/L), but not hyponatremia, hypochloremia (less than 80 mmol/L), or alkalemia. Left and right ventricular hypertrophy, multiple drug therapy, recurrent cyanotic episodes, and frequent unexplained fevers were common. In comparison with 17 bronchopulmonary dysplasia survivors who required longer than 60 days of ventilation therapy, the late deaths group more frequently had left ventricular hypertrophy and received prolonged combination theophylline anhydrous and beta-adrenergic agonist therapy. We report that sudden death can occur in infants with severe bronchopulmonary dysplasia despite in-hospital cardiopulmonary monitoring and the rapid institution of cardiopulmonary resuscitation, and is a significant cause of late mortality in infants who receive ventilation therapy for longer than 2 months.