Objective: To study the impact of low pulmonary vascular pressure on ventilator-induced lung injury. Design: Randomized prospective animal study. Subjects. Isolated perfused rabbit heart-lung preparation. Settings: Animal research laboratory in a university hospital. Interventions: Twenty isolated sets of normal lungs were perfused (constant flow, 0.3 L/min; left atrial pressure, 6 mm Hg), ventilated for 20 min (pressure control ventilation, 15 cm H2O; baseline period), and then randomized into three groups. Group A (control, n = 7) was perfused and ventilated as previously described during three consecutive 20-min periods. In group B (high airway pressure/normal left atrial pressure, n = 7), pressure control ventilation was 20, 25, and 30 cm H2O during each period. Group C (high airway pressure/low left atrial pressure, n = 6) was ventilated as group B but, in contrast to groups A and B, left atrial pressure was reduced to 1 mm Hg. Measurements and Main Results: The rate of edema formation (WGR, weight gain per minute normalized for initial lung weight) and the ultrafiltration coefficient (K-f) were measured during and after each period and their changes from baseline [DeltaWGR (edema formation index) and DeltaK(f) (vascular permeability index)] calculated to compare groups. The incidence and timing of vascular failure were compared. Vascular failure was considered to be present if all the following conditions were met: pulmonary hypertension, accelerated weight gain, and occurrence of fluid leak from the lungs. At the end of the study, DeltaWGR (g(.)g(-1.)min(-1)) was higher in group C (0.54 +/- 0.17) than in groups B (0.08 +/- 0.04) and A (0.00 +/- 0.01; p < .05), as well as in group B compared with A (p < .05). Similar differences between groups (p < .05) were found for DeltaK(f) (g(.)min(-1.)cm H(2)O(-1.)100g(-1)):C, 7.24 +/- 2.36; B, 1.40 +/- 0.49; A, 0.01 +/- 0.03. Vascular failure was not observed in groups A and B but occurred in all but one preparation in group C (p < .05; C vs. A and B). Conclusion: Reducing left atrial pressure results in more severe ventilator-induced lung injury. These results suggest that lung blood volume modulates cyclic tidal lung stress.