Endothelial cell proliferation and the formation of new vessels are strictly regulated by angiogenic factors (e.g., VEGF) that induce the activation of signal transduction pathways controlled by calcium dynamics. Using in vitro and in vivo experiments, we investigated the effect of calcium trifluoroacetate (CaTFAc), a complex, poorly dissociated salt that is characterized by its low toxicity, on angiogenesis. In vitro, CaTFAc inhibited VEGF-induced effects on endothelial cell proliferation. In two in vivo models of angiogenesis, a Matrigel plug in mice and a chick embryo chorioallantoic membrane, CaTFAc inhibited the VEGF-induced formation of new vessels. The exact mechanism of action is still under investigation, but in vitro experiments demonstrate that CaTFAc induced a reversible increase in the levels of intracellular calcium under basal conditions and prevented calcium signaling induced by VEGF. These results are the first to suggest that CaTFAc may be useful for the treatment of diseases caused by enhanced angiogenesis.