BACKGROUND: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The extent to which VEGF may cause tissue edema in humans has not been established. OBJECTIVE: To evaluate patients undergoing VEGF gene transfer for evidence of lower-extremity edema. DESIGN: Prospective consecutive case series. SETTING: Hospital outpatient clinic. PATIENTS: 62 patients with critical limb ischemia and 28 patients with claudication. INTERVENTION: Gene transfer of VEGF DNA. MEASUREMENTS: Semiquantitative analysis of lower-extremity edema. RESULTS: Lower-extremity edema was observed in 31 of 90 (34%) patients. Edema was less common in patients with claudication than in those with pain at rest (P = 0.016) or ischemic ulcers (P < 0.001), and it was less common in patients with pain at rest than in those with ischemic ulcers (P= 0.017). Treatment was typically limited to a brief course of oral diuretics. CONCLUSIONS: Vascular endothelial growth factor may enhance vascular permeability in humans. At the doses of plasmid DNA used in this study, lower-extremity edema responded to oral diuretic therapy and did not seem to be associated with serious sequelae.