Bone is continuously remodeled throughout life, and this remodeling is regulated by osteoclasts and osteoblasts. Bone-forming osteoblasts are derived from mesenchymal stem cells in bone marrow. Here, we have identified a new function of chlormadinone acetate (CMA) as an osteogenic activator in human bone marrow-derived mesenchymal stem cells (hBMSCs). To date, CMA has been used as an oral contraceptive and is known to have antiandrogenic activity. Our results show that CMA promotes osteoblast differentiation and calcium deposition in hBMSCs, whereas CMA treatment suppresses adipogenesis of hBMSCs. CMA activates and potentiates the phosphorylation of extracellular signal-regulated kinases (ERK1/2) in an osteogenic differentiation conditions. In addition, CMA-stimulated osteoblast differentiation is suppressed by inhibiting the ERK pathway, suggesting that CMA promotes the osteogenic differentiation program of hBMSCs through the ERK activation. Taken together, these results suggest a novel function of CMA as an osteogenic activator and intracellular signaling pathway mediated by CMA in osteoblast differentiation.