The separate effects of positive end-expiratory pressure (PEEP) and intravascular volume administration on the histopathologic lung injury were not investigated in experimental lung injury previously. The authors hypothesized that high PEEP and a restrictive volume therapy would yield the best oxygenation and the least degree of lung injury. Pigs (52.8 ± 3.4 kg) underwent saline lavage-induced lung injury. The animals were ventilated either with low PEEP (mean PEEP 9 to 12 cm H₂O) and liberal volume therapy using hydroxyethyl starch (LowP/Vol+) or high PEEP (mean PEEP 21 cm H₂O) combined with recruitment maneuvers and liberal (HighP/Vol+) or restrictive volume therapy (HighP/Vol-). After 6.5 hours, lung injury was determined by using a histopathologic score evaluating overdistension, edema, exsudation, and inflammation. When volume therapy was liberal, high PEEP (HighP/Vol+) improved the Pao₂/Fio₂ index (416 ± 80 mm Hg) compared to low PEEP (LowP/Vol+, 189 ± 55 mm Hg; P < .05) but there was no difference in the median (interquartile range) lung injury score: 1.6 (1.2-1.9) and 1.9 (1.4-2.0). High PEEP with restrictive volume therapy (HighP/Vol-) did not further improve oxygenation (400 ± 55 mm Hg) but ameliorated the degree of lung injury: 0.9 (0.8-1.4) (P < .05). In lavage-induced lung injury, high PEEP improved oxygenation, but restrictive volume administration markedly reduced the lung injury score, mainly by reduced edema.