Pulmonary blood flow (PBF) is a critical determinant of oxygenation during acute lung injury (ALI). PET/CT with (18)F-FDG allows the assessment of both lung aeration and neutrophil inflammation as well as an estimation of the regional fraction of blood (FB) if compartmental modeling is used to quantify (18)F-FDG pulmonary uptake. The aim of this study was to validate the use of FB to assess PBF, with PET and compartmental modeling of (15)O-H2O kinetics as a reference method, in both control animals and animals with ALI. For the purpose of studying a wide range of PBF values, supine and prone positions and various positive end-expiratory pressures (PEEPs) and tidal volumes (V(T)s) were selected. METHODS Pigs were randomized into 3 groups in which ALI was induced by HCl inhalation: pigs studied in the supine position with a low PEEP (5 ± 3 [mean ± SD] cm of H2O; n = 9) or a high PEEP (12 ± 1 cm of H2O; n = 8) and pigs studied in the prone position with a low PEEP (6 ± 3 cm of H2O; n = 9). Also included were a control group that did not have ALI (n = 6) and 2 additional groups (n = 6 each) that had a high V(T) to maintain a transpulmonary pressure of greater than or equal to 35 cm of H2O and that either received HCl inhalation or did not receive HCl inhalation. PBF and FB were measured with PET and compartmental modeling of (15)O-H2O and (18)F-FDG kinetics in 10 lung regions along the anterior-to-posterior lung dimension, and both were expressed in each region as a fraction of their values in the whole lung. RESULTS PBF and FB were strongly correlated (R(2) = 0.9), with a slope of the regression line close to unity and a negligible intercept. The mean difference between PBF and FB was 0, and the 95% limits of agreement were -0.035 to 0.035. This good agreement between methods was obtained in both normal and injured lungs and under a wide range of V(T), PEEP, and regional PBF values (7-71 mL/kg, 0-15 cm of H2O, and 24-603 mL·min(-1)·100 mL of lung(-1), respectively). CONCLUSIONS FB assessed with (18)F-FDG is a good surrogate for PBF in both normal animals and animals with ALI. PET/CT has the potential to be used to study ventilation, perfusion, and lung inflammation with a single tracer.