Lung recruitment maneuvers can help open collapsed lung units for sufficient oxygenation, and positive end expiratory pressure (PEEP) is used to keep the lung open after recruitment. However, the application of high PEEP levels may play a significant role in causing regional lung hyperinflation during mechanical ventilation. The authors sought to study the effects of PEEP targeting optimal oxygenation on regional lung volume distribution in a direct and an indirect acute respiratory distress syndrome (ARDS) model. ARDS was induced by either surfactant depletion or oleic acid injection in dogs. After lung recruitment, PEEP was decreased from 20 to 10 cmH2O in 2 cmH2O steps every 10 min to examine regional lung aeration by using computed tomography. Lung injury appeared to be localized in the model of surfactant depletion while it widely diffused after oleic acid infusion. At PEEP levels that achieved optimal oxygenation, nonaerated lung units decreased and normally aerated lung units enhanced, but hyperinflated areas increased significantly in both models (P < 0.05). Hyperinflated areas were greater in the surfactant depletion model than in the oleic acid model at PEEP levels applied (P < 0.05). Optimal oxygenation guided PEEP may cause hyperinflated in both focal lung injury and diffused lung injury post lung recruitment. Hyperinflation was more susceptible in focal lung injury than in diffused lung injury post lung recruitment.