OBJECTIVE To investigate the cardiorespiratory effects of graded bilateral pleural effusions in the anesthetized pig. METHODS Prospective, randomized, controlled, laboratory study. METHODS Animal laboratory. METHODS Eleven male Yorkshire pigs. METHODS Animals were anesthetized using inhaled isoflurane. Orotracheal intubation was followed by mechanical ventilation. Bilateral chest tubes were inserted, and graded increasing pleural effusions were created using saline of 0, 20, 40, and 80 mL/kg, divided equally between each side. At each pleural volume, intravascular volume was randomly altered (by phlebotomy or transfusion of colloid) to normal (unchanged), low (decreased by 10 mL/kg), or high (increased by 10 mL/kg). RESULTS Hemodynamic parameters, intrapleural pressures, hemoglobin, and blood gases were measured. At the lowest volume of pleural fluid, PaO2 was reduced by approximately 50% vs. baseline, whereas systemic hemodynamics were unchanged. PaO2 was reduced in a dose-dependent fashion as pleural volume increased but was not affected by alterations in intravascular volume. Intrapulmonary shunt was increased both by intrapleural volume in a dose-dependent fashion and by increases in intravascular volume at high levels of pleural volume. Cardiac output and systemic mean arterial pressure increased with elevated intravascular volume but were not influenced by lower levels of intrapleural volume. Mean pulmonary arterial pressure, central venous pressure, and pulmonary artery occlusion pressure were increased by elevations in both intrapleural volume and intravascular volume. Intrapleural pressure and pulmonary vascular resistance were related to intrapleural volume only. CONCLUSIONS Hypoxemia occurs as an early event in acute bilateral pleural effusions and precedes hemodynamic decompensation. Oxygenation is independent of intravascular filling pressures, but hemodynamics are preserved with elevated filling pressures. Clinical studies should be undertaken to examine the risks/benefits of careful removal of pleural fluid in patients with pleural effusions, when oxygenation is impaired during mechanical ventilation.