Objective: We hypothesized that a 50% increase in respiratory system elastance (Ers) would indicate similar degree of lung damage (equi-damage, ED), independently of ventilation strategy. Design and setting: A prospective, randomized animal laboratory investigation at a university hospital laboratory. Subjects: 35 anesthetized, paralyzed, mechanically ventilated male Sprague-Dawley rats. Interventions: Each rat was ventilated with a different combination of tidal volume, positive end-expiratory pressure, and inspired fraction of oxygen. Ers was determined throughout the experiment; the studies were interrupted when Ers reached 150% (ED) of its baseline value, or after 5 h. Measurements and results. Lung wet to dry weight ratio (W/D) was assessed. Morphological damage of the lung was scored on a grading of perivascular edema, hemorrhage, and breaks in the alveolar septa to obtain a total injury score. Twenty-four rats achieved an Ers of 150%: nine within 1 h (class 1), nine in 1-2 h (class 2), and six in 2-5 h (class 3). Eleven rats did not reach the target 50% increase in Ers (class 4). W/D was higher in rats that reached the target than in those that did not. W/D did not differ among rats that reached ED. Similarly, the total injury score did not differ among classes 1-3 but was higher than class 4. Conclusions: In the setting of VILI a 50% increase in Ers corresponds to an equal level of lung damage, irrespective of ventilatory setting and time of ventilation.