OBJECTIVE Pressure inflating the lung during mechanical ventilation is the difference between pressure applied at the airway opening (Pao) and pleural pressure (Ppl). Depending on the chest wall's contribution to respiratory mechanics, a given positive end-expiratory and/or end-inspiratory plateau pressure may be appropriate for one patient but inadequate or potentially injurious for another. Thus, failure to account for chest wall mechanics may affect results in clinical trials of mechanical ventilation strategies in acute respiratory distress syndrome. By measuring esophageal pressure (Pes), we sought to characterize influence of the chest wall on Ppl and transpulmonary pressure (PL) in patients with acute respiratory failure. METHODS Prospective observational study. METHODS Medical and surgical intensive care units at Beth Israel Deaconess Medical Center. METHODS Seventy patients with acute respiratory failure. METHODS Placement of esophageal balloon-catheters. RESULTS Airway, esophageal, and gastric pressures recorded at end-exhalation and end-inflation Pes averaged 17.5 +/- 5.7 cm H2O at end-expiration and 21.2 +/- 7.7 cm H2O at end-inflation and were not significantly correlated with body mass index or chest wall elastance. Estimated PL was 1.5 +/- 6.3 cm H2O at end-expiration, 21.4 +/- 9.3 cm H2O at end-inflation, and 18.4 +/- 10.2 cm H2O (n = 40) during an end-inspiratory hold (plateau). Although PL at end-expiration was significantly correlated with positive end-expiratory pressure (p < .0001), only 24% of the variance in PL was explained by Pao (R = .243), and 52% was due to variation in Pes. CONCLUSIONS In patients in acute respiratory failure, elevated esophageal pressures suggest that chest wall mechanical properties often contribute substantially and unpredictably to total respiratory impedance, and therefore Pao may not adequately predict PL or lung distention. Systematic use of esophageal manometry has the potential to improve ventilator management in acute respiratory failure by providing more direct assessment of lung distending pressure.