The members of the serine protease inhibitor (serpin) family, which share a common tertiary structure and a role as serin protease inhibitors, are involved in a variety of newly discovered functions. For example, antithrombin III exerts a strong antiangiogenic activity. Angiotensinogen, the renin substrate, has a folded structure and is a member of the noninhibitory serpin subfamily. Two other noninhibitory serpins, maspin and pigment epithelium-derived factor, have antiangiogenic properties. We investigated the antiangiogenic effect of angiotensinogen and 2 related compounds: (1) des(angiotensin I)angiotensinogen, the product of angiotensinogen cleavage by renin, and (2) the reactive center loop-cleaved angiotensinogen, which is produced after selective and limited proteolysis by the protease V8. We used well-established in vitro (endothelial cell proliferation and migration, and capillary-like tube formation on Matrigel) and in vivo (the chick chorioallantoic membrane assay) models of angiogenesis to evaluate the antiangiogenic activities of these 3 related molecules. Our data demonstrated that these compounds exerted a clear and equipotent antiangiogenic effect, thus attributing a novel function to angiotensinogen and des(angiotensin I)angiotensinogen, for which no function was previously known.