Background: Protective ventilation strategy has been shown to reduce ventilator-induced lung injury in patients with ARDS. In this study, we questioned whether protective ventilatory settings would attenuate lung impairment during one-lung ventilation (OLV) compared with conventional ventilation in patients undergoing lung resection surgery. Methods: One hundred patients with American Society of Anesthesiology physical status 1 to 2 who were scheduled for an elective lobectomy were enrolled in the study. During OLV, two different ventilation strategies were compared. The conventional strategy (CV group, n = 50) consisted of FIO2 1.0, tidal volume (VT) 10 mL/kg, zero end-expiratory pressure, and volume-controlled ventilation, whereas the protective strategy (PV group, n = 50) consisted of FIO2 0.5, VT 6 mL/kg, positive end-expiratory pressure 5 cm H2O, and pressure-controlled ventilation. The composite primary end point included PaO2/FIO2 < 300 mm Hg and/or the presence of newly developed lung lesions(lung infiltration and atelectasis) within 72 h of the operation. To monitor safety during OLV, oxygen saturation by pulse oximeter(SpO2), PaCO2, and peak inspiratory pressure(PIP) were repeatedly measured. Results: During OLV, although 58% of the PV group needed elevated FIO2 to maintain an SpO2 > 95%, PIP was significantly lower than in the CV group, whereas the mean PaCO2 values remained at 35 to 40 mm Hg in both groups. Importantly, in the PV group, the incidence of the primary end point of pulmonary dysfunction was significantly lower than in the CV group (incidence of PaO2/FIO 2 < 300 mm Hg, lung infiltration, or atelectasis: 4% vs 22%, P<.05). Conclusion: Compared with the traditional large VT and volume-controlled ventilation, the application of small VT and PEEP through pressure-controlled ventilation was associated with a lower incidence of postoperative lung dysfunction and satisfactory gas exchange. Trial registry: Australian New Zealand Clinical Trials Registry; No.: ACTRN12609000861257; URL: www.anzctr.org.au.