Both surfactant replacement and positive end-expiratory pressure (PEEP) increase lung volume in infants with respiratory distress syndrome (RDS). We measured pulmonary mechanics and functional residual capacity (FRC) in 21 preterm infants with RDS, > 48 hr post-surfactant therapy (BW, 1,168 +/- 441 g; GA, 28.3 +/- 2.8 weeks; postnatal age, 3-7 days). A non-linear but significant increase in mean FRC was noted as PEEP increased from 2 to 5 cmH2O: 18.4 +/- 4.7 mL/kg at 2 cmH2O; 19.7 +/- 4.3 mL at 3 cmH2O; 22.6 +/- 5.5 ml/kg at 4 cmH2O; and 26.2 +/- 6.2 mL/kg at 5 cmH2O (P < 0.01). Because of the synergistic combined effect on lung volume, surfactant treated neonates should be weaned cautiously from PEEP during ventilatory management. Our study also suggests that the occurrence of inadvertent end-distending pressure during FRC measurement in the ventilated neonate lead to erroneous results.