Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF‐TRAP_R1R2, in models for these disease processes. VEGF‐TRAP_R1R2 is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF‐TRAP_R1R2 strongly suppressed choroidal neovascularization in mice with laser‐induced rupture of Bruch's membrane. Subcutaneous injection of VEGF‐TRAP_R1R2 also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF‐induced breakdown of the blood–retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF‐TRAP_R1R2 significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF‐TRAP_R1R2 may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema. © 2003 Wiley‐Liss, Inc.