BACKGROUND: We previously demonstrated a markedly dependent distribution of ventilator-induced lung injury in oleic acid-injured supine animals ventilated with large tidal volumes and positive end-expiratory pressure > or =10 cm H2O. Because pleural pressure distributes more uniformly in the prone position, we hypothesized that the extent of injury induced by purely mechanical forces applied to the lungs of normal animals might improve and that the distribution of injury might be altered with prone positioning. OBJECTIVE: To compare the extent and distribution of histologic changes and edema resulting from identical patterns of high end-inspiratory/low end-expiratory airway pressures in both supine and prone normal dogs. DESIGN/SETTING: We ventilated 10 normal dogs (5 prone, 5 supine) for 6 hrs with identical ventilatory patterns (a tidal volume that generated a peak transpulmonary pressure of 35 cm H2O when implemented in the supine position before randomization, positive end-expiratory pressure = 3 cm H2O). Ventilator-induced lung injury was assessed by gravimetric analysis and histologic grading. MEASUREMENTS AND MAIN RESULTS: Wet weight/dry weight ratios (WW/DW) and histologic scores were greater in the supine than the prone group (8.8+/-2.8 vs. 6.1+/-0.7; p = .01 and 1.4+/-0.3 vs. 1+/-0.3; p = .037, respectively). In the supine group, WW/DW and histologic scores were significantly greater in dependent than nondependent regions (9.4+/-1.9 vs. 6.7+/-0.9; p = .01 and 2.0+/-0.4 vs. 0.9+/-0.4; p = .043, respectively). In the prone group, WW/DW also was greater in dependent regions (6.7+/-1.1 vs. 5.8+/-0.5; p = .054), but no significant differences were found in histologic scores between dependent and nondependent regions (p = .42). CONCLUSION: In this model of lung injury induced solely by mechanical forces, the prone position resulted in a less severe and more homogeneous distribution of ventilator-induced lung injury. These results parallel those previously obtained in oleic acid-preinjured animals ventilated with higher positive end-expiratory pressure.