Objective Vascular calcification (VC), which refers to ectopic mineralization in vascular cells occurs frequently in many diseases such as chronic kidney disease (CKD), atherosclerosis, and diabetes. VC is vastly correlated with high risk of cardiovascular morbidity and mortality, due to arterial stiffness and impaired vascular compliance. Estrogen-related receptor gamma (ERRg), a member of orphan nuclear receptor superfamily is shown to be related to bone formation. However, role of ERRg in VC has not yet been investigated. This study was undertaken to examine the role of ERRg in VC. Methods RT-PCR, Western blot, Von kossa's staining, Promoter assay. Results ERRg was upregulated during inorganic phosphate (Pi)-induced calcification of vascular smooth muscle cell (VSMC), along with increased expression of bone morphogenic protein-2 (BMP2), osteocalcin and alkaline phosphatase (ALP). Transient overexpression of ERRg stimulated promoter activity of osteogenic genes such as BMP2 and osteocalcin. Adenovirus- mediated overexpression of ERRg also augmented osteogenic gene expression and exacerbates Pi-induced calcification of VSMC. Moreover, inhibition of ERRg by a selective inverse agonist attenuated both Pi-induced osteogenic gene expression and calcium deposition in cultured VSMC. Finally, ex vivo aortic tissue culture showed that the ERRg inverse agonist. significantly reduced Pi-induced calcification in mouse aorta. These results demonstrate that ERRg stimulates VC by upregulating osteogenic genes Conclusion Our findings suggest that inhibition of ERRg may be a potential therapeutic strategy for prevention of vascular calcification.