Background: Preterm infants often receive mechanical ventilation and oxygen at birth. Exposure to large tidal volumes (VT s) at birth causes lung inflammation, and oxygen may amplify the injury. We hypothesized that normal VT ventilation at birth causes lung injury that is exacerbated by 95% oxygen. Methods: The head and chest of anesthetized preterm fetal sheep (129 ± 1 d gestation) were surgically exteriorized while maintaining the placental circulation. Fetuses were randomized to four groups with either V T ventilation to 6 ml/kg or continuous positive airway pressure of 5 cm H2 O, and either 95%O 2/5%CO2 or 95%N 2/5%CO 2. Age-matched fetuses were used as controls. After a 15-min intervention, the fetal lamb was returned to the uterus for 1h 45 min.Results:In ventilated lambs, VT was 6.2 ± 0.4 ml/kg at 15 min. Ventilation increased proinflammatory cytokines as compared with controls and lambs on continuous positive airway pressure, with recruitment of primarily monocytes to bronchoalveolar lavage fluid. Early response protein 1 was activated around the bronchioles in VT-ventilated animals. The 15-min oxygen exposure did not change inflammatory mediators or other markers of lung and oxidative stress. Conclusion: A VT of 6-7 ml/kg at birth increased early markers of injury and lung inflammation. Brief exposure to 95% oxygen did not alter lung inflammation.