Osteoprotegerin (OPG) is a soluble tumor necrosis factor receptor family member that is expressed by a range of cell types in bone as well as in the vasculature. However, the specific role of OPG in the vascular system is unclear. We recently reported that OPG treatment protects endothelial cells from detachment and apoptotic cell death induced by cysteine proteases of Porphyromonas gingivalis, an important pathogen of adult periodontitis. We also found that OPG activates the extracellular signal-regulated kinase (ERK) 1/2, which has been linked to cell survival and angiogenesis. In this study, we demonstrate that exposure to OPG induces a substantial morphological change in human dermal microvascular endothelial cells. Our results show that OPG induced a dose-dependent increase in the length of microtubules, which coincided with the transition of the cells from a polygonal to an elongated shape. Furthermore, we demonstrated that OPG activates signaling pathways that lead to the activation of Src, focal adhesion kinase, and ERK1/2. These findings suggest that OPG regulates at least two distinct pathways: one that induces cell proliferation via ERK signaling and another that induces angiogenesis via Src signaling. The findings of this study suggest that OPG may function as a regulator of angiogenesis.