Background: This study was designed to evaluate the potential role of osteoprotegerin (OPG) in arterial fibrosis. Methods: Aortic samples were analyzed after in vivo treatment of ApoE−/− mice with recombinant human OPG. Mouse vascular smooth muscle cells (VSMC) were exposed in vitro to recombinant OPG and analyzed for markers of inflammation and fibrosis, such as fibronectin, collagen I, III, IV and transforming growth factor-1 (TGF-1). Conversely, the potential modulation of endogenous OPG expression and release by VSMC was analyzed in response to different pro-atherosclerotic cytokines, TGF-1, platelet derived growth factor (PDGF) and angiogensin II (Ang II). Results: In vivo treatment with human OPG induced signs of fibrosis and up-regulated the arterial expression of TGF-1. Consistently, in vitro treatment of VSMC with human OPG induced the expression of fibronectin, collagen type I, III, IV, metalloprotein-2 (MMP-2) and MMP-9, as well as of TGF-1. On the other hand, exposure to recombinant TGF-1 promoted the expression/release of endogenous OPG and mediated the increase of OPG release induced by PDGF and Ang II in VSMC. Conclusions: Taken together, these data support a pathogenic role for OPG in the development and progression of atherosclerotic lesions and suggest the existence of a vicious circle between TGF-1 and OPG.