Acute respiratory distress syndrome continues to be associated with significant morbidity and mortality related to ventilation-perfusion mismatch, pulmonary hypertension, and right ventricular failure. It has been suggested that inhaled nitric oxide, which is a selective pulmonary vasodilator, may be effective in the treatment of acute respiratory distress syndrome; however, the effects of nitric oxide on cardiopulmonary interactions are poorly understood. We therefore developed a model of acute lung injury that mimics the clinical syndrome of acute respiratory distress syndrome. In our model, inhaled nitric oxide significantly reduced pulmonary artery pressure, pulmonary vascular resistance, and pulmonary vascular impedance. In addition, inhaled nitric oxide improved transpulmonary vascular efficiency and ventilation-perfusion matching, which resulted in increased arterial oxygen tension. Although arterial oxygen tension increased, oxygen delivery did not improve significantly. These data suggest that by improving ventilation-perfusion matching and arterial oxygen tension while lowering pulmonary vascular resistance and impedance, nitric oxide may be beneficial in patients with acute respiratory distress syndrome. However, additional measures to enhance cardiac performance may be required.