Combretastatin A4 phosphate (CA4P) is currently undergoing clinical trials as a tumor vascular-targeting agent. Here, we defined the antivascular effect and programmed cell death (PCD) induced by CA4P in vascular endothelial cells. CA4P induced time- and dose-dependent antiproliferative activities against human umbilical vein endothelial cells (HUVECs), and caused G2/M arrest accompanied with DNA fragmentation. The in vitro wound assay and tube formation assay indicated that CA4P potently inhibited migration of endothelial cells and tube formation. The apoptosis and autophagy marker microtubule-associated protein light chain 3 (LC3)-II was induced in CA4P-treated HUVECs. The current study demonstrates that CA4P is a promising antivascular agent with potent PCD-inducing activities. CA4P may be useful in the treatment of cancer and hemangioma.