Although PEEP and inversed I:E ratio have been shown to improve gas exchange in ARDS, both can adversely affect systemic hemodynamics and cerebral perfusion. The goal of this study was to assess how changes in PEEP and I:E ratio affect systemic and cerebral oxygenation and perfusion in normal and injured lung.Eight anesthetized Chinchilla-Bastard rabbits were ventilated at baseline with pressure-regulated volume control mode, VT = 6 ml/kg, PEEP = 6 cmH2O, FIO2 = 0.4; respiratory rate set for ETCO2 = 5.5%, and I:E = 1:2, 1:1 or 2:1 in random order. Ultrasonic carotid artery flow (CF), arterial (PaO2), jugular venous blood gases and near infrared spectroscopic cerebral oxygenation (∆HBO2) were recorded for each experimental condition. After induced lung injury, the animals were ventilated with PEEP = 9 followed by 6 cmH2O.At baseline, inverse-ratio ventilation (IRV) significantly reduced cerebral oxygenation (∆O2HB; - 27 at 1:2; - 15 at 1:1 vs. 0.27 μmol/L at 2:1; p < 0.05), due to a significant reduction in mean arterial pressure and CF without modifying gas exchange. In injured lung, IRV improved gas exchange but decreased cerebral perfusion without affecting brain oxygenation. The higher PEEP level, however, improved PaO2 (67.5 ± 19.3 vs. 42.2 ± 8.4, p < 0.05), resulting in an improved ∆HBO2 (- 13.8 ± 14.7 vs. -43.5 ± 21.3, p < 0.05), despite a drop in CF.Our data suggest that unlike moderate PEEP, IRV is not effective in improving brain oxygenation in ARDS. In normal lung, IRV had a deleterious effect on brain oxygenation, which is relevant in anesthetized patients.