OBJECTIVE Previously published methods to assess the chest wall effect on total respiratory system pressure-volume (P-V) curves in acute respiratory distress syndrome have been performed on the lung and chest wall in isolation. We sought to quantify the effect of the chest wall by considering the chest wall and lung in series. DESIGN Prospective study. SETTING Academic health center medical and surgical intensive care units. PATIENTS Twenty-two patients with acute respiratory distress syndrome/acute lung injury. INTERVENTIONS Using a sigmoidal equation, we fit the pressure-volume data of the lung alone, and defined for each curve the pressure at the point of maximum compliance increase (Pmci), decrease (Pmcd), and the point of inflection (Pinf). We calculated the pressure to which the total respiratory system must be inflated to achieve a volume that would place the lung at each point of interest. We compared these "corrected" pressures (Pmci,c, Pmcd,c, and Pinf,c) to the measured values of the total respiratory system. MEASUREMENTS AND MAIN RESULTS The average difference between Pmci and Pmci,c was 0.12 cm H2O on inflation (2sd = 5.6 cm H2O) and -1.4 cm H2O on deflation (2sd = 5.0 cm H2O); between Pmcd and Pmcd,c was 1.73 cm H2O on inflation (2sd = 4.5 cm H2O) and -0.15 cm H2O on deflation (2sd = 4.9 cm H2O); and between Pinf and Pinf,c was 0.14 cm H2O on inflation (2sd = 6.7 cm H2O) and -0.35 cm H2O on deflation (2sd = 5.0 cm H2O). CONCLUSIONS This method of "correcting" the total respiratory system P-V curve for the chest wall allows for calculation of an airway pressure that would place the lung at a desired volume on its P-V curve. For most patients, the chest wall had little influence on the total respiratory system P-V curve. However, there were patients in whom the chest wall did potentially have clinical significance.