Objective: Osteoprotegerin (OPG), a member of the TNF (tumor necrosis factor) receptor superfamily, is a key regulator of osteoclastogenesis. Recently, we reported that endothelial cells produce high level of OPG in response to Escherichia coli lipopolysaccharide¹. We also indicated that OPG treatment protects human microvascular endothelial cells (HMVECs) from detachment and apoptotic cell death induced by cysteine proteases that are produced by Porphyromonas gingivalis². These results suggest that OPG can be involved in the immunological functions of endothelial cells. However, the potential role of OPG in endothelial cell biology is unknown. In this study, we investigated the effects of OPG on HMVECs. Methods: HMVECs were seeded in 96-well plates and incubated for 36 h in human serum-free medium (H-SFM) with increasing doses of OPG (20,100 and 500 ng/ml). Cell proliferation was assessed by a tetrazolium (WST-8) reduction assay. Cell migration was assessed using FALCON Cell Culture FluoroBlok Inserts, which are inserts coated with vitronectin or fibronectin. Two integrin receptors for vitronectin, namely, integrin α_vβ₃ and α_vβ₅are expressed on endothelial cells; in certain experiments, therefore, cells in suspension were pre-treated with anti-α_vβ₃ or anti-α_vβ₅ antibodies. Results: The OPG treatment induced the proliferation of HMVECs in a dose-dependent manner. The cell migration assay showed that OPG induced cell migration on vitronectin in a dose-dependent manner, whereas no significant increase in migration occurred on fibronectin. In addition, a blocking antibody to α_vβ₃, but not to α_vβ₅, significantly inhibits OPG-induced cell migration. These results indicate that OPG promotes α_vβ₃-dependent endothelial cell migration. Conclusions: Our results reveal that the OPG is an important factor for the proliferation and migration of endothelial cells. Because integrin α_vβ₃ is highly expressed in angiogenic endothelial cells but not in quiescent endothelial cells, our results also suggest that OPG can regulate the migration of endothelial cells by influencing α_vβ₃ expression. This suggests that OPG plays a role in neovessel formation under physiological and pathological conditions.