Respiratory failure is a major contributor to mortality and morbidity in newborn infants. The lung assist device (LAD) is a novel gas exchange device that supplements mechanical ventilation. The objective is to test the effect of the LAD on pulmonary histopathology in juvenile piglets with acute lung injury caused by saline lung lavage (SLL) followed by intermittent mandatory ventilation (IMV). Three-to 4-wk-old piglets were randomized to no intervention (control group), SLL alone (SLL group), SLL ϩ IMV (IMV group), or SLL ϩ IMV ϩ LAD (LAD group) (n ϭ 6 per group). The carotid artery and jugular vein were cannulated and an arteriovenous circuit completed, and the LAD was inserted into this circuit. Gas exchange via the LAD was initiated by passage of 100% oxygen over the blood-carrying hollow fibers of the LAD. Hemodynamic variables were recorded. Mechanical ventilation was systematically weaned. Lung histology was scored by two observers masked to treatment group. There were no differences in hemodynamic variables between the study groups. There was a significant increase in the total lung injury score in the IMV group compared with the LAD group. The novel pumpless low-resistance LAD has shown feasibility and potential to decrease ventilator-induced lung injury in a juvenile animal model. (1-3) associated with high morbidity, mortality, and cost (4 -6). The mainstay of management is supportive care with mechanical ventilation, and important adjunctive therapies include high-frequency ventilation, surfactant therapy, inhaled nitric oxide, and extracorporeal membrane oxygenation (ECMO). Many term and preterm infants die due to cardiorespiratory failure despite maximal ventilatory support (3-10). It is well known that ventilatory support by itself may inflict lung injury (11,12). Animal and human studies indicate that volutrauma contributes to the development of lung injury (13-15). ECMO, a treatment of last resort for term or near-term neonates with profound cardiopulmonary disease, allows the lung to rest and recover, attenuating the often damaging effects of aggressive mechanical ventilation. However, ECMO is currently reserved for newborn infants with reversible pulmonary disease in whom conventional or high-frequency ventilation with inhaled nitric oxide has failed. This is due to serious inherent risks of ECMO, such as coagulopathy and the need for systemic anticoagulation, which predisposes to systemic and intracranial hemorrhage. An essential element in the ECMO circuit is a mechanical pump that directly leads to shear stress-induced injury of blood cells (16). The evolution of membrane and oxygenator technology has led to low-resistance membrane gas exchange devices that permit significant flow even when the circuit is not driven by a pump. Several investigators have reported the ability of these devices to partially support adult patients in respiratory failure. Gattinoni et al. (17) proved the efficacy and safety of extracorporeal carbon dioxide removal in combination with low-frequency ven...