OBJECTIVE: To investigate the effects of the rate of increase in airway pressure and duration of lung recruitment maneuvers in experimental pulmonary and extrapulmonary acute lung injury. DESIGN: Prospective, randomized, controlled experimental study. SETTINGS: University research laboratory. SUBJECTS: Fifty adult male Wistar rats. INTERVENTIONS: Acute lung injury was induced by Escherichia coli lipopolysaccharide either intratracheally (pulmonary acute lung injury) or intraperitoneally (extrapulmonary acute lung injury). After 24 hours, animals were assigned to one of three different recruitment maneuvers, targeted to maximal airway pressure of 30 cm H2O: 1) continuous positive airway pressure for 30 seconds (CPAP-30); 2) stepwise airway pressure increase (5 cm H2O/step, 8.5 s at each step) over 51 seconds (STEP-51) to achieve a pressure-time product similar to that of CPAP-30; and 3) stepwise airway pressure increase (5 cm H2O/step, 5 s at each step) over 30 seconds with maximum pressure sustained for a further 30 seconds (STEP-30/30). MEASUREMENTS AND MAIN RESULTS: All recruitment maneuvers reduced static lung elastance independent of acute lung injury etiology. In pulmonary acute lung injury, CPAP-30 yielded lower surfactant protein-B and higher type III procollagen expressions compared with STEP-30/30. In extrapulmonary acute lung injury, CPAP-30 and STEP-30/30 increased vascular cell adhesion molecule-1 expression, but the type of recruitment maneuver did not influence messenger ribonucleic acid expression of receptor for advanced glycation end products, surfactant protein-B, type III procollagen, and pro-caspase 3. CONCLUSIONS: CPAP-30 worsened markers of potential epithelial cell damage in pulmonary acute lung injury, whereas both CPAP-30 and STEP-30/30 yielded endothelial injury in extrapulmonary acute lung injury. In both acute lung injury groups, recruitment maneuvers improved respiratory mechanics, but stepwise recruitment maneuver without sustained airway pressure appeared to associate with less biological impact on lungs.