Pulmonary vascular resistance was investigated in the fluorocarbon-filled lung in an in situ isolated lung preparation. Lungs were perfused at constant flow (100 ml X min-1 X kg-1) with whole blood from a donor cat. left atrial pressure was held constant at zero pressure. Measurements of pulmonary arterial pressure enabled calculation of pulmonary vascular resistance. Regional changes in pulmonary blood flow were determined by the microsphere technique. During quasi-static deflation over a range of 0-30 mmHg, dependent alveolar pressure was consistently greater for a volume of fluorocarbon than for gas, with each pressure-volume curve for the fluorocarbon-filled lung shifted to the right of the curve for the gas-filled lung. In turn, pulmonary vascular resistance was found to increase linearly as a function of increasing alveolar pressure, independent of the medium in the lung. Thus, for a given volume, pulmonary vascular resistance was consistently greater in the fluorocarbon-filled lung compared with the gas-filled lung. This increase in pulmonary vascular resistance was accompanied by a redistribution of pulmonary blood flow in which blood flow to the dependent region was decreased in the fluorocarbon-filled lung compared with the gas-filled lung. Conversely, the less-dependent regions of the lung received a relatively greater percentage of blood flow when filled with fluorocarbon compared with gas. These findings suggest that pulmonary vascular resistance is increased during liquid ventilation, largely as the result of mechanical interaction at the alveolar-vascular interface.