We have measured regional pulmonary blood flow (PBF) in normal dogs with positron emission tomography (PET) and 15O-labeled water (H2(15)O). The method is nondestructive, quantitative, and repeatable. To measure PBF, PET is used to measure both the initial and equilibrium distribution of lung activity after H2(15)O infusion. The data are then interpreted with a one-compartment mathematical model. Measurements of PBF in dogs with H2(15)O (PBF-water) were compared with PBF measured with 68Ga microspheres (PBF-MS), and a close correlation was observed: PBF-water = 0.82 PBF-MS + 25.4 (R = 0.97, n = 52). In another set of animals an important assumption of the method, namely that the tracer is fully extracted during a single pass through the lung, was demonstrated using a single-probe residue-detection technique. Computer simulations were performed to illustrate the sensitivity of the method to errors in the measured variables of tracer activity or tissue-blood partition coefficient. Results showed only small error magnification for the range of values observed in these studies.