VEGF and TGF-beta1 induce angiogenesis but have opposing effects on endothelial cells. VEGF protects endothelial cells from apoptosis; TGF-beta1 induces apoptosis. We have previously shown that VEGF/VEGF receptor-2 (VEGFR2) signaling mediates TGF-beta1 induction of apoptosis. This finding raised an important question: Does this mechanism stimulate or inhibit angiogenesis? Here we report that VEGF-mediated apoptosis is required for TGF-beta1 induction of angiogenesis. In vitro the apoptotic effect of TGF-beta1 on endothelial cells is rapid and followed by a long period in which the cells are refractory to apoptosis induction by TGF-beta1. Inhibition of VEGF/VEGFR2 signaling abrogates formation of cord-like structures by TGF-beta1 with an effect comparable to that of z-VAD, an apoptosis inhibitor. Similarly, genetic deficiency of VEGF abolishes TGF-beta1 upregulation of endothelial cell differentiation and formation of vascular structures in embryoid bodies. In vivo TGF-beta1 induces endothelial cell apoptosis as rapidly as in vitro. Inhibition of VEGF blocks TGF-beta1 induction of both apoptosis and angiogenesis, an effect similar to that of z-VAD. Thus, TGF-beta1 induction of angiogenesis requires a rapid and transient apoptotic effect mediated by VEGF/VEGFR2. This novel, unexpected role of VEGF and VEGFR2 indicates VEGF-mediated apoptosis as a potential target to control angiogenesis.