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Cardiac catheterization studies have demonstrated that Doppler-derived flow velocities in the ductal flow jet and the left pulmonary artery accurately predict the aortopulmonary pressure difference and left-to-right shunt size in newborns. To assess the presence of persistent pulmonary hypertension in premature newborns with various degrees of respiratory distress syndrome (RDS) severity, we estimated pulmonary artery pressure from the aortopulmonary pressure difference and pulmonary blood flow from the left pulmonary artery flow velocity with color-flow-directed, pulsed Doppler echocardiography. Seventy-nine premature neonates were divided into three groups—no or mild RDS (n = 27), severe RDS (n = 38), and fatal RDS (n = 14)—and compared with a group of healthy term neonates (n = 34). In premature and term neonates with no/mild RDS the mean ± SEM aortopulmonary pressure difference increased from 7.3 ± 0.4 and 6.6 ± 0.5 mm Hg to 22.8 ± 1.4 and 21.4 ± 1.1 mm Hg over the first 24 hours (P < .001). The mean aortopulmonary pressure difference was 0.9 ± 0.3 mm Hg during the first 72 hours in neonates with fatal RDS, but increased from 1.5 ± 0.3 mm Hg at 4 hours to 7.4 ± 0.6 at 24 hours and 21.5 ± 0.7 mm Hg at 72 hours of age in neonates with severe RDS. Left pulmonary artery velocity time integrals were 18.3 ± 0.5 cm in premature and 18.8 ± 0.5 cm in term neonates with no/mild RDS at 12 hours vs 11.2 ± 0.4 cm in neonates with severe and 9.9 ± 0.5 cm in neonates with fatal RDS (P < .001). At 36 hours of age pulmonary blood flow velocity in neonates with severe RDS had caught up with that of those with no/mild RDS, but was only 11.6 ± 0.6 cm in neonates with fatal RDS (P < .001). These data indicate that persistent pulmonary hypertension and large right-to-left shunts via the ductus are common findings in small premature neonates with severe RDS and are predictive of early demise.