Intratracheal lipopolysaccharide (LPS) causes acute inflammation and injurious mechanical ventilation results in pulmonary and systemic inflammation. We aimed to determine in preterm lungs if continuous positive airway pressure (CPAP) protects against pulmonary and systemic inflammation, compared with conventional mechanical ventilation (CMV) after intratracheal LPS. Preterm fetuses were exposed to maternal betamethasone and Epostane 36 h before delivery at 133 d gestational age (term ϭ 150 d). Lambs were intubated and randomized to receive gentle CMV (tidal volume 8 mL/kg) or CPAP with 8 cm H 2 O pressure. Surfactant (10 mg/kg) mixed with 1 mg LPS or saline was instilled into the trachea at 15 min. Blood gas status, ventilation variables, and arterial pressures were recorded for 3 h. Static pressure-volume curves and lung and systemic inflammation were assessed postmortem. CPAP lambs had elevated Paco 2 and minute ventilation compared with the CMV lambs. Cytokine mRNA was increased in the lungs and liver of CPAP and CMV lambs relative to unventilated controls. Intratracheal LPS amplified the cytokine mRNA responses of IL-1, IL-6, and IL-8 in the lung and liver. Blood neutrophils decreased similarly after LPS in CPAP and CMV groups. Cytokine markers of lung injury or the systemic response to intratracheal LPS were not decreased by CPAP relative to CMV, in preterm lambs. . Similarly, ventilation with lung volumes that approach or exceed total lung capacity will stretch the lungs and cause injury (3,4). The preterm fetal lung is particularly vulnerable to lung injury during the transition from a fluid-filled lung to airway breathing because surfactant deficiency increases the pressures required to open the lung, the lung aerates nonuniformly, and the delicate tissues of the preterm lung are easily stretched (5,6). The use of continuous positive airway pressure (CPAP) is being advocated for transitioning the preterm fetal lung to air breathing as a way to decrease lung injury (7,8). Although CPAP can cause lung injury in sepsis models (9), CPAP can decrease indicators of lung injury in preterm lambs (10) compared with conventional mechanical ventilation (CMV) and its use has been associated with decreased bronchopulmonary dysplasia (11).Prior exposure of the adult lung to pro-inflammatory mediators such as endotoxin amplifies lung injury caused by ventilation from low lung volumes or elevated lung volumes (9,12,13), and the mediators can enter the systemic circulation and cause systemic inflammatory responses (14,15). Termventilated lambs do not leak endotoxin from the airspaces into the systemic circulation unless the lungs are over-stretched (16). In contrast, preterm lungs leak endotoxin or IL-1 with conventional ventilation (16,17). Chorioamnionitis is associated with many preterm deliveries before 32 wk gestational age, and inflammatory mediators are present in the fetal lung (18,19). We hypothesized that spontaneous breathing with CPAP would protect the preterm lung and minimize a systemic inflamma...