Although a right-to-left shunt via a patent ductus arteriosus is one criterion for the diagnosis of persistent pulmonary hypertension of the newborn infant, it cannot be demonstrated by simultaneous pre- and postductus arteriosus blood oxygen tensions in many infants with the clinical syndrome. In animals, exposure of the fetal ductus arteriosus to salicylates causes contriction and results in pulmonary hypertension. We postulated that maternal ingestion of salicylates and premature closure of the ductus arteriosus may explain why some infants with PPHN do not have right-to-left ductus shunts. Therefore, we studied serum salicylate levels in six groups of infants: I, normal infants' cord blood (0.73 +/- 0.44 mg/dl, N = 20); Ia, normal infants at 24 to 36 hours of age (0.08 +/- 0.1 mg/dl, N = 5): II, other cardiopulmonary diseases with no right-to-left ductus shunt (2.08 +/- 1.74 mg/dl, N = 26); III, other cardiopulmonary diseases and right-to-left ductus shunt (2.34 +/- 1.70 mg/dl, delta Pao2 70 +/- 71 mm Hg, N = 6); IV, PPHN and right-to-left ductus shunt (1.86 +/- 1.51 mg/dl, delta Pao2 39.6 +/- 58.9 mm Hg, N = 5); V, PPHN without right-to-left ductus shunt (7.77 +/- 5.18 mg/dl, delta Pao2 2.2 +/- 1.5 mm Hg, N = 6). Serum salicylate levels were significantly greater (P less than 0.01) in infants with PPHN without right-to-left ductus shunt, indicating that the ductus arteriosus may have been closed prematurely. No other factor, including serum bilirubin, amikacin, ampicillin, or furosemide levels, could be found to account for the difference in serum salicylate levels. Premature closure of the ductus arteriosus secondary to maternal ingestion of salicylates may be one cause of PPHN and may explain the absence of right-to-left ductus shunting in some infants with the clinical syndrome.