The reason why some infants with respiratory distress syndrome fail to respond to surfactant, or respond only transiently, is incompletely understood. We hypothesized that resuscitation with large breaths at birth might damage the lungs and blunt the effect of surfactant. Five pairs of lamb siblings were delivered by cesarean section at 127-128 d of gestation. One lamb in each pair was randomly selected to receive six manual inflations of 35-40 mL/kg ("bagging") before the start of mechanical ventilation, a volume roughly corresponding to the inspiratory capacity of lamb lungs after prophylactic surfactant supplementation. Both siblings were given rescue porcine surfactant, 200 mg/kg, at 30 min of age. Blood gases and deflation pressure-volume (P-V) curves of the respiratory system were recorded until the lambs were killed at 4 h. The P-V curves became steeper after surfactant in the control group, but no such effect was seen in those subjected to bagging. At 4 h, inspiratory capacity and maximal deflation compliance were almost three times higher (p < 0.01) in the controls than in the bagged lambs. The latter were also more difficult to ventilate and tended to have less well expanded alveoli and more widespread lung injury in histologic sections. We conclude that a few inflations with volumes that are probably harmless in other circumstances might, when forced into the surfactant-deficient lung immediately at birth, compromise the effect of subsequent surfactant rescue treatment. Our findings challenge current neonatal resuscitation practice of rapidly establishing a normal lung volume by vigorous manual ventilation.