Mechanical ventilation may promote overdistension-induced pulmonary lesions in patients with acute respiratory distress syndrome (ARDS). The static pressure-volume (P-V) curve of the respiratory system can be used to determine the lung volume and corresponding static airway pressure at which lung compliance begins to diminish (the upper inflection point, or UIP). This fall in compliance may indicate overdistension of lung units. We prospectively studied 42 patients receiving mechanical ventilation with an FIO2 of 0.5 or more for at least 24 h. According to the Lung Injury Score (LIS), 25 patients were classified as having ARDS (LIS > 2.5), while 17 patients constituted a non-ARDS control group. The P-V curve was obtained every 2 d. Mechanical ventilation initially used standard settings (volume-control mode, a positive end-expiratory pressure [PEEP] adjusted to the lower inflection point on the P-V curve, and a tidal volume [VT] of 10 ml/kg). The end-inspiratory plateau pressure (Pplat) was compared to the UIP, and VT was lowered when the Pplat was above the UIP. In the range of lung volume studied on the P-V curves (up to 1600 mi), a UIP could be shown in only one control patient (at 23 cm H2O). By contrast, a UIP was present on the P-V curve obtained from all patients with ARDS, corresponding to a mean airway pressure of 26 +/- 6 cm H2O, a lung volume of 850 +/- 200 ml above functional residual capacity and 610 +/- 235 ml above PEEP. During the course of ARDS, Pplat rose above the UIP in 20 (80%) of the 25 patients (Pplat of 31 +/- 5 cm H2O, range 22 to 48, compared with UIP of 24 +/- 4 cm H2O, range 18 to 37, p < 0.001). In these patients, VT was reduced by 2.2 +/- 0.9 ml/kg (1 to 4.2 ml/kg) in an attempt to keep Pplat below the UIP. This induced a rise in Pa-CO2 from 44 +/- 10 to 77 +/- 25 mm Hg (p < 0.01) but no change in the Pa-O2/FIO2 ratio. We conclude that a UIP can be demonstrated in all patients with ARDS and that 80% of them would need a reduction in VT based on this criterion; this strategy may result in marked hypercapnia, without a significant change in oxygenation.