Continuous positive airway pressure (CPAP) is being used clinically to avoid mechanical ventilation of preterm infants as a strategy to minimize lung injury. There is little experimental information about how CPAP might minimize lung injury after preterm birth. We induced preterm labor in antenatal glucocorticoid-treated sheep carrying twins at 133 d gestation with an inhibitor of progesterone synthesis. The lambs delivered spontaneously approximately 2 d later and were randomized to three groups: no ventilation (n = 4), conventional mechanical ventilation to a target PCO(2) of 40 mm Hg (n = 5), or CPAP using a bubble CPAP device set to deliver 5 cm H(2)O pressure (n = 6). The CPAP lambs breathed without distress and maintained PCO(2) values of approximately 60 mm Hg. At 2 h of age, the lungs of the CPAP lambs held 74 +/- 4 mL/kg air at 40 cm H(2)O pressure, which was more than the 60 +/- 3 mL/kg for the ventilated lambs (p < 0.05). Lymphocyte and monocyte numbers in alveolar washes were equivalent in the unventilated, ventilated, and CPAP lambs. However, no neutrophils were found in the unventilated lambs, and the ventilated lambs had 6.6 times more neutrophils in alveolar washes than did the CPAP lambs (p < 0.05). The cells in alveolar wash from CPAP lambs contained less hydrogen peroxide than did the cells from ventilated lambs (p < 0.05). In this model in preterm lambs CPAP results in lower indicators of acute lung injury than does mechanical ventilation during the first 2 h of life.