We hypothesized that the angiogenic mediator, vascular endothelial growth factor (VEGF), known to be expressed in the lung and to be capable of inducing local edema in skin, might evoke the development of lung edema if expressed in excess amounts. To test this hypothesis, we developed an in vivo model of VEGF overexpression in the lung on the basis of delivery to the respiratory epithelium of the VEGF165 complementary DNA by an E1 2 adenovirus vector (AdVEGF165). Administration of AdVEGF165 by the intratracheal route (10 9 plaque-forming units [pfu]) to C57Bl/6 mice showed increased expression of VEGF messenger RNA in lung tissue by Northern analysis. Overexpression of VEGF protein in the lung at Days 1 to 10 was confirmed by enzyme-linked immunosorbent assay. Intratracheal administration of AdVEGF165 resulted in a dose-dependent increase in lung wet/dry weight ratios over time, lung histology showed widespread intraalveolar edema, and pulmonary capillary permeability was significantly increased as quantified by the Evans blue dye assay and [ 131 I]albumin permeability. To confirm the specificity of these observations, mice were pretreated with intranasal administration of an adenovirus vector expressing a truncated soluble form of the VEGF receptor flt-1 (Ad sflt ). Ad sflt (10 9 pfu) pretreatment completely abrogated the increased lung wet/dry weight ratio caused by AdVEGF165 administration, whereas an identical adenovirus vector with an irrelevant transgene had no effect upon subsequent AdVEGF165-induced pulmonary edema. Together, these data suggest that overexpression of VEGF in the lung may be one mechanism of increased pulmonary vascular permeability in the early stages of acute lung injury. Pulmonary edema, defined as an excessive amount of extravascular water in the lungs, is a common clinical problem that occurs when fluid is filtered into the lungs faster than it is removed (1‐5). The major consequence of pulmonary edema is in the gas exchange units, where swelling of the alveolar interstitium and flooding of the alveoli cause disturbances in lung mechanical functions and gas exchange (6‐8). Although there are many causes of pulmonary edema, the pathophysiology of pulmonary edema can be generally classified as that due to increased pressure (e.g., heart failure) or due to increased permeability (e.g., adult respiratory distress syndrome [ARDS]) (9, 10). In the “increased permeability” category, more than 100 initiating agents have been described, all of which are associated with an alteration in the integrity of the barrier to the flow of protein and fluid into the lungs (9). This barrier is provided by the 70-m 2 continuous, nonfenestrated capillary bed, in which the endothelium is held together by tight junctions forming a “gasket-like” seal (11, 12). The barrier to protein and fluid flow into the alveolar intersti