The optimal setting for positive end-expiratory pressure (PEEP) in mechanical ventilation remains controversial in the treatment of acute respiratory distress syndrome (ARDS). The aim of this study was to determine the optimum PEEP level in ARDS, which we defined as the level that allowed the best arterial oxygen delivery (DO2). We conducted a physiologic multicenter prospective study on patients who suffering from ARDS according to standard definition and persistent after 6 hours of ventilation. The PEEP was set to 6 cm H2O at the beginning of the test and then was increased by 2 cm H2O after at least 15 minutes of being stabilized until the plateau pressure achieved 30 cm H2O. At each step, the cardiac output was measured by transesophageal echocardiography and gas blood was sampled. We were able to determine the optimal PEEP for 12 patients. The ratio of PaO2/FiO2 at inclusion was 131 ± 40 with a mean FiO2 of 71 ± 3%. The optimal PEEP level was lower than the higher PEEP despite a constant increase in SaO2. The optimal PEEP levels varied between 8 and 18 cm H2O. Our results show that in patients with ARDS the optimal PEEP differs between each patient and require being determined with monitoring.