Pathological angiogenesis is the most common cause of vision loss at all ages including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration. ROP is a proliferative disease of the retinal vasculature in premature infants. Herein, we demonstrated caffeic acid (CA) has the anti-angiogenic activity to retinal endothelial cells and retinal neovascularization in a mouse model of ROP, which might be related to the suppression of ROS-induced VEGF expression. CA effectively inhibited VEGF-induced proliferation of retinal endothelial cells in concentration-dependent manner. In addition, VEGF-induced migration and tube formation of retinal endothelial cells were completely inhibited. This anti-angiogenic activity of CA on retinal endothelial cells was related to the anti-oxidant activity: the inhibitory activity of CA to H(2)O(2)-induced reactive oxygen species production and VEGF expression. Interestingly, CA significantly suppressed retinal neovascularization in oxygen-induced retinopathy as the animal model of ROP without retinal cytotoxicity. These data suggests that CA could be a potent anti-angiogenic agent for retinal neovascularization, and be applied in the treatment of other vaso-proliferative retinopathies.