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We evaluated the effect of two quality improvement interventions (low tidal volume ventilation and restrictive transfusion) on the development of acute lung injury in mechanically ventilated patients.Observational cohort study.Three intensive care units in a tertiary academic center.We included patients who were mechanically ventilated for ≥48 hrs excluding those who refused research authorization or had preexisting acute lung injury or pneumonectomy.Multifaceted interdisciplinary intervention consisting of Web-based teaching, respiratory therapy protocol, and decision support within computerized order entry.Of 375 patients who met the inclusion and exclusion criteria, 212 were ventilated before and 163 after the interventions. Baseline characteristics were similar between the two groups except for a lower frequency of sepsis (27% vs. 17%, p = .030), trend toward lower median glucose level (140 mg/dL, interquartile range 118–168 vs. 132 mg/dL, interquartile range 113–156, p = .096), and lower frequency of pneumonia (27% vs. 20%, p = .130) during the second period. We observed a large decrease in tidal volume (10.6–7.7 mL/kg predicted body weight, p < .001), in peak airway pressure (31–25 cm H2O, p < .001), and in the percentage of transfused patients (63% to 38%, p < .001) after the intervention. The frequency of acute lung injury decreased from 28% to 10% (p < .001). The duration of mechanical ventilation decreased from a median of 5 (interquartile range 4–9) to 4 (interquartile range 4–8) days (p = .030). When adjusted for baseline characteristics in a multivariate logistic regression analysis, protocol intervention was associated with a reduction in the frequency of new acute lung injury (odds ratio 0.21, 95% confidence interval 0.10–0.40).Interdisciplinary intervention effectively decreased large tidal volumes and unnecessary transfusion in mechanically ventilated patients and was associated with a decreased frequency of new acute lung injury.