We identified seventeen infants with Down syndrome without structural congenital heart disease who presented with persistent pulmonary hypertension in the newborn period. Respiratory distress with or without hypoxia was the presenting feature in these infants. Pulmonary hypertension resolved in the majority of the survivors. Two infants with refractory pulmonary hypertension benefited from patent ductus arteriosus ligation. Autopsies in two infants demonstrated structural lung immaturity. We suggest that infants with Down syndrome are at risk of developing persistent pulmonary hypertension even in the absence of structural heart disease and these infants should be followed up until resolution of the pulmonary hypertension.