Vascular endothelial cells receive proangiogenic or antiangiogenic signals from components of extracellular matrix (ECM) depending upon the situation and many molecular signals can have opposite effects in different vascular beds. Tissue inhibitor of metalloproteinase 1 is antiangiogenic in several tissues, but promotes retinal neovascularization. When cleaved from native collagens, several of the non-collagenous domains (NC1) of basement membrane collagens have antiangiogenic effects in some tissues, but this is context dependent for the NC1 of the alpha 1 chain of collagen IV. It is critical to examine effects in several well-defined model systems before assuming that an ECM component is universally antiangiogenic. In this study, we examined the effects of a recombinant fragment of NC1 of the alpha 2 chain of type IV collagen (α2(IV)NC1) in a well-characterized model of ocular neovascularization. Intravitreous or periocular injections of α2(IV)NC1 caused selective apoptosis of endothelial cells participating in neovascularization resulting in suppression of neovascularization when the peptide was given prior to onset of new vessel sprouting. Importantly, when the peptide was given after neovascularization had already developed, it caused the new vessels to regress. This suggests that α2(IV)NC1, which has previously been shown to suppress tumor angiogenesis in xenograft models, is also a strong antiangiogenic agent in the choroid and is a therapeutic candidate for treatment of neovascular age-related macular degeneration. © 2006 Wiley-Liss, Inc.