OBJECTIVES: Although pleural effusion reduces respiratory system compliance by restricting the lungs, the effusion volume is partially accommodated by chest wall expansion. The implications for these opposing volume changes on airway pressure monitoring in ventilated patients with pleural effusion are unreported. We investigated the interactions among pleural effusion, positive end-expiratory pressure, and indices of respiratory mechanics in a swine model. DESIGN: Interventional animal model. SETTING: Hospital animal research facility. SUBJECTS: Nine deeply anesthetized swine. INTERVENTIONS: The preparation included tracheostomy, arterial/venous catheter placement, and chest tube insertion. Animals were ventilated throughout the study at 9 mL/kg, and frequency was adjusted to maintain normocapnia (inspiratory:expiratory=1:2, FIO2=0.5) and positive end-expiratory pressure of 1 cm H2O and 10 cm H2O. Fluid was instilled into the right pleural space to simulate effusions of 13 mL/kg (pleural effusion 1) and 26 mL/kg (pleural effusion 2). MEASUREMENTS AND MAIN RESULTS: Quantitative computerized tomography studies (in five animals) and functional residual capacity volumes (wash-in/wash-out technique) were obtained for each pleural effusion/positive end-expiratory pressure combination. Mean functional residual capacity compared to baseline at positive end-expiratory pressure of 1 cm H2O was decreased by pleural effusion 1 and pleural effusion 2 (-42%, -64%) and restored by positive end-expiratory pressure of 10 cm H2O (moderate) to +23% of baseline for pleural effusion 1 and +1% for pleural effusion 2. Plateau pressure increased and compliance decreased in response to pleural effusion 1 and pleural effusion 2. Moderate positive end-expiratory pressure applied during both pleural effusion quantities restored plateau pressure and tidal compliance to prepleural effusion values. Computed tomography studies revealed lung compression and tidal derecruitment cycles occurring with pleural effusion at positive end-expiratory pressure of 1 cm H2O, whereas a moderate positive end-expiratory pressure restored prepleural effusion functional residual capacity and prevented lung and intratidal derecruitment. CONCLUSIONS: When pleural effusion is present, respiratory mechanics must be interpreted cautiously and sufficient positive end-expiratory pressure should be applied to prevent extensive collapse and intratidal cycles of recruitment/derecruitment.