β(2)-glycoprotein I (β(2)-GPI) is a plasma glycoprotein with diverse functions, but the impact and molecular effects of β(2)-GPI on vascular biology are as yet unclear. Based on the limited information available on the contribution of β(2)-GPI to endothelial cells, we investigated the effect of β(2)-GPI on cell growth and migration in human aortic endothelial cells (HAECs). The regulation of β(2)-GPI as part of intracellular signaling in HAECs was also examined. Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor that may regulate endothelial functions. We found that β(2)-GPI dose-dependently inhibited VEGF-induced endothelial cell growth using the 3-(4,5-dimethylthiazol-2-yl)-2,5-dipenyl tetrazolium bromide assay and cell counts. Using wound healing and Boyden chamber assays, β(2)-GPI remarkably reduced VEGF-increased cell migration at the physiological concentration. Furthermore, β(2)-GPI suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2), extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt. These results suggest that β(2)-GPI plays an essential role in the down-regulation of VEGF-induced endothelial responses and may be a useful component for anti-angiogenic therapy.