The neovascular form of the age-related macular degeneration (AMD) causes most cases of severe blindness. Because vascular endothelial growth factor (VEGF) plays a leading role in this disorder, several inhibitors of this molecule are being used in its treatment. However, VEGF has important functions in vascular pathophysiology. It enhances the development of collateral vessels that may supply blood to areas whose arteries are severely affected by atherosclerotic lesions. Additionally, it may promote restoration of the damaged endothelium, a vessel layer that protects against the development of atherothrombosis, and it has hypotensive effects. In contrast, VEGF may stimulate the formation of microvessels inside the atherosclerotic plaque. These vessels may become disrupted and cause intraplaque hemorrhage, stimulating disease progression. VEGF also has a role in thrombus formation. The effects of anti-VEGF therapy may therefore compromise patient safety. When administered systemically to cancer patients, the main cardiovascular adverse effects of these compounds have been thrombosis, hemorrhage and hypertension. As patients with AMD constitute a high-risk population for cardiovascular events, the safety of new anti-VEGF therapies must be assessed. In this review we analyze the effects of VEGF on atherosclerosis and the cardiovascular safety of anti-VEGF therapies in AMD.