OBJECTIVE: Mechanical ventilation causes cyclic changes in the heart's preload and afterload, thereby influencing the circulation. However, our understanding of the exact physiology of this cardiopulmonary interaction is limited. We aimed to thoroughly determine airway pressure distribution, how this is influenced by tidal volume and chest compliance, and its interaction with the circulation in humans during mechanical ventilation. DESIGN: Intervention study. SETTING: ICU of a university hospital. PATIENTS: Twenty mechanically ventilated patients following coronary artery bypass grafting surgery. INTERVENTION: Patients were monitored during controlled mechanical ventilation at tidal volumes of 4, 6, 8, and 10 mL/kg with normal and decreased chest compliance (by elastic binding of the thorax). MEASUREMENTS AND MAIN RESULTS: Central venous pressure, airway pressure, pericardial pressure, and pleural pressure; pulse pressure variations, systolic pressure variations, and stroke volume variations; and cardiac output were obtained during controlled mechanical ventilation at tidal volume of 4, 6, 8, and 10 mL/kg with normal and decreased chest compliance. With increasing tidal volume (4, 6, 8, and 10 mL/kg), the change in intrathoracic pressures increased linearly with 0.9 ± 0.2, 0.5 ± 0.3, 0.3 ± 0.1, and 0.3 ± 0.1 mm Hg/mL/kg for airway pressure, pleural pressure, pericardial pressure, and central venous pressure, respectively. At 8 mL/kg, a decrease in chest compliance (from 0.12 ± 0.07 to 0.09 ± 0.03 L/cm H2O) resulted in an increase in change in airway pressure, change in pleural pressure, change in pericardial pressure, and change in central venous pressure of 1.1 ± 0.7, 1.1 ± 0.8, 0.7 ± 0.4, and 0.8 ± 0.4 mm Hg, respectively. Furthermore, increased tidal volume and decreased chest compliance decreased stroke volume and increased arterial pressure variations. Transmural pressure of the superior vena cava decreased during inspiration, whereas the transmural pressure of the right atrium did not change. CONCLUSIONS: Increased tidal volume and decreased chest wall compliance both increase the change in intrathoracic pressures and the value of the dynamic indices during mechanical ventilation. Additionally, the transmural pressure of the vena cava is decreased, whereas the transmural pressure of the right atrium is not changed.