Obesity is characterized by elevated pleural pressure (P) and worsening atelectasis during mechanical ventilation in patients with acute respiratory distress syndrome (ARDS). To determine the effects of lung recruitment maneuver (LRM) in the presence of elevated P on hemodynamics, left and right ventricular pressures and pulmonary vascular resistance. We hypothesized that elevated P protects the cardiovascular system against high airway pressures and prevents lung overdistension. First, an interventional crossover trial in adult subjects with ARDS and BMI ≥35 kg/m (n=21) was performed to explore the hemodynamic consequences of LRM. Second, cardiovascular function was studied during low/high PEEPs in a model of swine with ARDS and high P (n=9) versus healthy swine with normal P (n=6). Subjects with ARDS and obesity (BMI=57±12 kg/m), following LRM, required an increase in PEEP of 8[7, 10] cmHO above traditional ARDSnet settings to improve lung function, oxygenation and ventilation/perfusion matching, without impairment of hemodynamics or right heart function. ARDS swine with high P demonstrated unchanged transmural left ventricle pressure and systemic blood pressure after LRM protocol. Pulmonary artery hypertension decreased 8[13, 4] mmHg, as did vascular resistance 1.5[2.2, 0.9] WU, and transmural right ventricle pressure 10[15, 6] mmHg during exhalation. LRM and PEEP decreased pulmonary vascular resistance and normalized ventilation/perfusion ratio. High airway pressure is required to recruit lung atelectasis in patients with ARDS and class III obesity but causes minimal overdistension. Additionally, patients with ARDS and class III obesity tolerate hemodynamically LRM with high airway pressure.