It is currently not known whether vaporized perfluorohexane may be superior to partial liquid ventilation (PLV) for the therapy of acute lung injury. In this work, we aimed at comparing the effects of both therapies in oleic acid induced lung injury. Lung injury was induced in thirty anesthetized and mechanically ventilated pigs by means of central venous infusion of oleic acid. Animals were assigned to one of the following groups: 1) control or gas ventilation (GV); 2) 2.5 % perfluorohexane vapor; 3) 5 % perfluorohexane vapor; 4) 10 % perfluorohexane vapor and 5) PLV with perfluorooctane (30 ml/kg). Two hours after randomization, lungs were recruited and positive end-expiratory pressure was adjusted to obtain minimal elastance (open lung approach). Ventilation was continued during 4 additional hours, when animals were killed for lung histologic examination. Gas exchange and elastance were comparable among vaporized perfluorohexane, PLV and GV before the open lung approach was used and improved in a similar fashion in all groups after positive end-expiratory pressure was adjusted to optimal elastance (p < 0.05). A similar behavior was observed in the functional residual capacity in animals treated with vaporized perfluorohexane and GV. Lung resistance improved after recruitment (p < 0.05), but values were higher in the perfluorohexane 10 % and PLV groups, as compared to GV (p < 0.05). Interestingly, positive end-expiratory pressure values required to obtain minimal elastance were lower with 5 % perfluorohexane than PLV and GV (p <0.05). Diffuse alveolar damage was significantly lower in the 5 % and 10 % perfluorohexane vapor groups, as compared to PLV and GV (p < 0.05). Analysis of distribution of effects revealed that alveolar damage was lower with 5 % perfluorohexane than with GV or PLV in the non-dependent (p<0.001 and p<0.0001, respectively), as well as in central regions (p<0.0001 and p<0.001, respectively). In peripheral regions, 5 % perfluorohexane led to reduced alveolar damage (p<0.05), as compared to GV. In dependent regions, alveolar damage was lower with 5 % perfluorohexane and PLV as compared to GV (p<0.0001). Gas ventilated and animals treated with 5 % perfluorohexane showed less alveolar damage in the non-dependent as compared to dependent regions (p<0.001 and p<0.05, respectively), whereas PLV presented the opposite pattern (p<0.05). Oxidative stress was decreased with 5 % perfluorohexane as compared to GV (p<0.05). None of these perfluorcarbon therapies improved gas exchange or lung mechanics, as compared to GV. However, the use of 5 % vaporized perfluorohexane permitted to reduce pressures needed to stabilize the lungs and was associated with better histologic findings than PLV and GV. Whereas PLV led to more pronounced effects in dependent than in non-dependent regions, 5 % vaporized perfluorohexane showed the opposite pattern. Despite this gravity-related characteristic, 5 % vaporized perfluorohexane attenuated alveolar damage as efficiently as PLV in dependent regions and also reduced the oxidative stress in the lungs. Vaporized perfluorohexane may prove an alternative to PLV to reduce alveolar damage in acute lung injury.