Inflammation during mechanical ventilation is thought to depend on regional mechanical stress. This can be produced by concentration of stresses and cyclic recruitment in low-aeration dependent lung. Positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) allows for noninvasive assessment of regional metabolic activity, an index of neutrophilic inflammation. We tested the hypothesis that, during mechanical ventilation, surfactant-depleted low-aeration lung regions present increased regional 18F-FDG uptake suggestive of in vivo increased regional metabolic activity and inflammation. Sheep underwent unilateral saline lung lavage and were ventilated supine for 4 h (positive end-expiratory pressure = 10 cmH2O, tidal volume adjusted to plateau pressure = 30 cmH2O). We used PET scans of injected 13N-nitrogen to compute regional perfusion and ventilation and injected 18F-FDG to calculate 18F-FDG uptake rate. Regional aeration was quantified with transmission scans. Whole lung 18F-FDG uptake was approximately two times higher in lavaged than in nonlavaged lungs (2.9 ± 0.6 vs. 1.5 ± 0.3 10−3/min; P < 0.05). The increased 18F-FDG uptake was topographically heterogeneous and highest in dependent low-aeration regions (gas fraction 10–50%, P < 0.001), even after correction for lung density and wet-to-dry lung ratios. 18F-FDG uptake in low-aeration regions of lavaged lungs was higher than that in low-aeration regions of nonlavaged lungs ( P < 0.05). This occurred despite lower perfusion and ventilation to dependent regions in lavaged than nonlavaged lungs ( P < 0.001). In contrast, 18F-FDG uptake in normally aerated regions was low and similar between lungs. Surfactant depletion produces increased and heterogeneously distributed pulmonary 18F-FDG uptake after 4 h of supine mechanical ventilation. Metabolic activity is highest in poorly aerated dependent regions, suggesting local increased inflammation.