OBJECTIVE: To determine the influence of clinician-adjustable ventilator settings on the development of ventilator-induced lung injury, as assessed by changes in gas exchange (Pao2), compliance, functional residual capacity, and wet weight to dry weight ratio. DESIGN: Randomized in vivo rabbit study. SETTING: Hospital research laboratory. SUBJECTS: Forty-four anesthetized, mechanically ventilated adult rabbits. INTERVENTIONS: Ventilation for 2 hrs with pressure control ventilation at 45 cm H2O, Fio2 = 0.6, and randomization to one of five ventilatory strategies using combinations of positive end-expiratory pressure (3 or 12 cm H2O), inspiratory time (0.45, 1.0, or 2.0 secs), and frequency (9 or 23/min). MEASUREMENTS AND MAIN RESULTS: Among the ventilator strategies applied, PEEP at 12 cm H2O (elevated positive end-expiratory pressure) and inspiratory time at 0.45 secs (reduced inspiratory time) best preserved Pao2 (p <.003) and compliance (p <.035). During injury development, two consistent changes were observed: Tidal volume increased, and airway pressure waveform was transformed by extending the time to attain target pressure. CONCLUSIONS: In this preclinical model, lung injury was attenuated by decreasing inspiratory time. As lung injury occurred, tidal volume increased and airway pressure waveform changed.