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The effects of prone positioning on esophageal pressures have not been investigated in mechanically ventilated patients. Our objective was to characterize effects of prone positioning on esophageal pressures, transpulmonary pressure, and lung volume, thereby assessing the potential utility of esophageal pressure measurements in setting positive end-expiratory pressure (PEEP) in prone patients.We studied 16 patients undergoing spine surgery during general anesthesia and neuromuscular blockade. We measured airway pressure, esophageal pressures, airflow, and volume, and calculated the expiratory reserve volume and the elastances of the lung and chest wall in supine and prone positions.Esophageal pressures at end expiration with 0 cm H2O PEEP decreased from supine to prone by 5.64 cm H2O (95% CI, 3.37 to 7.90; P < 0.0001). Expiratory reserve volume measured at relaxation volume increased from supine to prone by 0.15 l (interquartile range, 0.25, 0.10; P = 0.003). Chest wall elastance increased from supine to prone by 7.32 (95% CI, 4.77 to 9.87) cm H2O/l at PEEP 0 (P < 0.0001) and 6.66 cm H2O/l (95% CI, 3.91 to 9.41) at PEEP 7 (P = 0.0002). Median driving pressure, the change in airway pressure from end expiration to end-inspiratory plateau, increased in the prone position at PEEP 0 (3.70 cm H2O; 95% CI, 1.74 to 5.66; P = 0.001) and PEEP 7 (3.90 cm H2O; 95% CI, 2.72 to 5.09; P < 0.0001).End-expiratory esophageal pressure decreases, and end-expiratory transpulmonary pressure and expiratory reserve volume increase, when patients are moved from supine to prone position. Mean respiratory system driving pressure increases in the prone position due to increased chest wall elastance. The increase in end-expiratory transpulmonary pressure and expiratory reserve volume may be one mechanism for the observed clinical benefit with prone positioning.