Transcription factor Ets-1 is induced in endothelial cells (ECs) by angiogenic factors, and promotes angiogenesis by inducing angiogenesis-related genes such as MMPs and integrin Β3. Here, we examined the effect of Ets-1 on apoptosis in ECs. Overexpression of Ets-1 in human umbilical vein endothelial cells (HUVECs) induced apoptosis under the serum-deprived condition. VEGF inhibited apoptosis and augmented the DNA binding of Ets-1 in HUVECs. The inhibition of transcriptional activity of endogenous Ets-1 by a dominant negative molecule intensified the anti-apoptotic effect of VEGF. Caspase inhibitors blocked apoptosis of HUVECs induced by Ets-1. DNA array analysis showed that Ets-1 up-regulated pro-apoptotic genes such as Bid, cytochrome p450, caspase-4, p27, and p21 more than 2 fold, and down-regualted anti-apoptotic genes such as DAD-1, AXL, Cox-2, IAP-2, and MDM-2 less than 0.5 fold in HUVECs. These results indicate that Ets-1 itself is pro-apoptotic to ECs by modulating the expression of apoptosis-related genes.