Rationale: Mechanical ventilation, often required to maintain normal gas exchange in critically ill patients, may cause lung injury itself. Lung-protective ventilatory strategies with low tidal volume have been a major success in the management of acute respiratory distress syndrome (ARDS). Volutrauma causes mechanical injury and induces an acute inflammatory response. Objectives: To determine whether neutrophil elastase (NE), a potent proteolytic enzyme in neutrophils, would contribute to ventilator-induced lung injury. Methods: Neutrophil elastase deficient (NE^-/-) and wild-type mice were mechanically ventilated at set tidal volumes (10, 20, and 30 ml/kg) with 0 cmH2O of PEEP for 3 hours. Lung physiology and markers of lung injury were measured. Neutrophils from wild-type and NE^-/- mice were also used for in vitro studies of neutrophil migration, ICAM-1 cleavage, and endothelial cell injury. Results: Surprisingly, in the absence of NE, mice were not protected, but developed worse ventilator-induced lung injury despite having lower number of neutrophils in alveolar spaces. The possible explanation for this finding is that NE cleaves ICAM-1 allowing neutrophils to egress from the endothelium. In the absence of NE, impaired neutrophil egression and prolonged contact between neutrophils and endothelial cells leads to tissue injury and increased permeability. Conclusions: NE is required for neutrophil egression from the vasculature into the alveolar space, and interfering with this process leads to neutrophil-related endothelial cell injury.