Early studies suggest that transient tachypnea of the newborn is a benign disease of uncertain etiology. Consequently, prevention of this complication has not been a primary concern of obstetricians. In this study of amniotic fluid phospholipids, 55 pregnancies in which the neonate developed transient tachypnea were compared to 355 pregnancies after which respiratory distress did not occur. Thirteen neonatal complications and procedures, often associated with prematurity, were significantly increased in the infants who developed transient tachypnea. Potential risk factors for transient tachypnea were examined by stepwise discriminant analysis. Negative amniotic fluid phosphatidylglycerol, prematurity (less than 38 weeks), and 1-minute Apgar score less than 7 all made an independent contribution to the overall characterization of infants at increased risk for transient tachypnea. These findings suggest that mild fetal lung immaturity may be a factor in the pathophysiology of this syndrome, and that the relationship of perinatal factors associated with transient tachypnea of the newborn in previous studies, including maternal diabetes mellitus and cesarean birth, may be partially mediated through a neonatal surfactant deficiency.