Ventilator settings influence the development and outcome of acute lung injury. This study investigates the influence of low versus high tidal volume (V t ) on oxidative stress-induced lung injury.Isolated rabbit lungs were subjected to one of three ventilation patterns (V t -positive end-expiratory pressure, PEEP): LVZP (6 ml/kg-0 cm H 2 O), HVZP (12 ml/kg-0 cm H 2 O), LV5P (6 ml/kg-5 cm H 2 O). These ventilation patterns allowed a comparison between low and high V t without dependence on peak inspiratory pressure (PIP). Infusion of hypochlorite (1000 nmol/min) or buffer (control) was started at t=0 min. Pulmonary artery pressure (PAP), PIP and weight were continuously recorded. Capillary filtration coefficient [K f , c (10 - 4 ml s - 1 cm H 2 O - 1 g - 1 )] was gravimetrically determined (-15/30/60/90/120 min).PIP averaged 5.8+/-0.6/13.9+/-0.6/13.9+/-0.4 cm H 2 O in the LVZP, HVZP and LV5P groups. PIP, K f , c or PAP did not change in control groups, indicating that none of the ventilation patterns caused lung injury by themselves. Hypochlorite-induced increase in K f , c but not hypochlorite-induced increase in PAP, was significantly attenuated in the LVZP-/LV5P- versus the HVZP-group (K f , c , m a x . 1.0+/-0.23/1.4+/-0.40 versus 3.2+/-1.0*). Experiments with hypochlorite were terminated due to excessive edema (>50 g) at 97+/-2.2/94.5+/-4.5 min in the LVZP-/LV5P-group versus 82+/-3.8* min in the HVZP-group (*: P<0.05).Low V t attenuated oxidative stress-induced increase in vascular permeability independently from PIP and PEEP.