Introduction: Mechanical ventilation delivers energy (mechanical work) to the respiratory system at each breath. We used an animal model of high pressure-volume ventilation to determine if a relationship exists between energy delivered to the respiratory system and development of ventilator-induced lung injury. Methods: Fifteen piglets were ventilated with different energy loads, obtained with constant tidal volume (38±3 ml/kg, strain >2.5) and different respiratory rates (3-6-9-12-15 breaths/min). The study protocol lasted 54 hours or less if massive lung edema developed. At the beginning of the study, a dynamic pressure-volume curve of the respiratory system was obtained to determine the energy delivered per minute (energy delivered per breath times respiratory rate). Endexpiratory CT-scans were performed at baseline and at the end of the study to measure the increase in lung weight during mechanical ventilation. Results: Energy delivered per minute to the respiratory system ranged from 3.0 J/min to 28.5 J/min (median 15.5 J/min). A ROC curve analysis showed that an energy delivered of 16.7 J/min had 100% sensitivity and 100% specificity in predicting an increase in lung weight greater than 10% at the end of the study. Figure 1 shows the relationship between the energy delivered per minute and the percentage increase in lung weight. Conclusions: In our model of high pressure-volume ventilation it was possible to identify an energy threshold above which mechanical ventilation caused ventilator-induced lung injury.