Two relatively large premature newborn infants with respiratory distress syndrome and ductus-dependent congenital heart disease were treated. In one, pharmacologic closure of the ductus arteriosus resulted in severe hypoxemia. The patency of the ductus as reestablished with the infusion of alprostadil (PGE1), until palliative surgery was performed. In the second case, persistent pulmonary hypertension was clinically suspected, and pharmacologic therapy was initiated without adequate cardiac evaluation. In large premature infants with respiratory distress syndrome, closure of the ductus arteriosus should not be attempted before ruling out the presence of ductus-dependent congenital heart disease. Furthermore, pharmacologic closure of ductus arteriosus can be reversed by the infusion of prostaglandin.