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To analyze the effect on clinical outcomes of prophylactic positive end expiratory pressure in nonhypoxemic ventilated patients.Multicenter randomized controlled clinical trial.One trauma and two general intensive care units in two university hospitals.One hundred thirty-one mechanically ventilated patients with normal chest radiograph and Pao2/Fio2 above 250.Patients were randomly allocated to receive mechanical ventilation with 5–8 cm H2O of positive end-expiratory pressure (PEEP) (PEEP group, n = 66) or no-PEEP (control group, n = 65).Primary end-point variable was hospital mortality. Secondary outcomes included microbiologically confirmed ventilator-associated pneumonia, acute respiratory distress syndrome, barotrauma, atelectasis, and hypoxemia (Pao2/Fio2 <175). Both groups were similar at randomization in demographic characteristics, intensive care unit admission diagnoses, severity of illness, and risk factors for ventilator-associated pneumonia. Hospital mortality rate was similar (p = 0.58) between PEEP (29.7%) and control (25.4%) groups. Ventilator-associated pneumonia was detected in 16 (25.4%) patients in the control group and 6 (9.4%) in the PEEP group (relative risk, 0.37; 95% confidence interval = 0.15–0.84; p = 0.017). The number of patients who developed hypoxemia was significantly higher in the control group (34 of 63 patients, 54%) than in the PEEP group (12 of 64, 19%) (p < 0.001), and the hypoxemia developed after a shorter period (median [interquartile range]) in the control group than in the PEEP group (38 [20–70] hrs vs. 77 [32–164] hrs, p < 0.001). Groups did not significantly differ in incidence of acute respiratory distress syndrome (14% in controls vs. 5% in the PEEP group, p = 0.08), barotrauma (8% vs. 2%, respectively, p = 0.12), or atelectasis (27% vs. 19%, respectively, p = 0.26).These findings indicate that application of prophylactic PEEP in nonhypoxemic ventilated patients reduces the number of hypoxemia episodes and the incidence of ventilator-associated pneumonia.