It is not clear if low end-expiratory pressures contribute to ventilator-induced lung injury in large animals. We sought to determine whether ventilation with a low level of positive end-expiratory pressure (PEEP) worsens preexisting permeability lung injury in dogs. Lung injury was initiated in 20 mongrel dogs by ventilating with nebulized 3N hydrochloric acid until a lower inflection point (LIP) appeared on the respiratory system pressure-volume loop. One group of 10 dogs was then ventilated for 4 hours with PEEP set below the LIP (low PEEP), whereas the remaining group of dogs was ventilated for the same time period with similar tidal volumes but with PEEP set above the LIP (high PEEP). We found histologic evidence of reduced alveolar volumes in the low-PEEP animals. However, there were no differences in neutrophil infiltration, lung lobe weights, pulmonary capillary hemorrhage or congestion, or arterial endothelin-1 concentration between the 2 protocol groups. In conclusion, we were unable to demonstrate that ventilation with PEEP set below the LIP exacerbates hydrochloric acid-induced lung injury in dogs.