Postmenopausal osteoporosis is characterized by decreased bone quality and mineral density. Mesenchymal stem cells (MSCs) found in the bone marrow, are pluripotent cells able to differentiate into several phenotypes, including osteoblasts and adipocytes. In osteoporosis, MSCs' commitment and differentiation into osteoblast/adipocyte is unbalanced, favoring adipocyte formation. The osteo and adipogenic processes are modulated by the bone morphogenetic protein-2 (BMP-2). This cytokine regulates the expression of transcription factors PPARγ and Runx 2, but its action on cells under adipogenic conditions is poorly understood. In this work we studied BMP-2 signaling in MSCs obtained from bone marrow of control or osteoporotic volunteer postmenopausal women. MSCs were cultured under basal, adipogenic (AD) or AD plus BMP-2 conditions. The protein content of PPARγ, p-PPARγ, Runx2, bone morphogenetic receptor IA (BMPR IA), phosphorylated Smad-1/5/8 (p-Smad) and Smad 4 were determined by specific western blots. mRNA level for BMPRs was determined by PCR and cell localization of p-Smad-1/5/8 were detected by immunocytochemistry. Control MSCs showed a differential response to both AD and AD plus BMP-2 treatments: BMP-2 exerted an anti-adipogenic effect increasing both transcription factors analyzed. Moreover, p-Smads-1/5/8 were detected in nuclei after short term BMP-2 treatment. Osteoporotic MSCs showed no response to exogenous added BMP-2, as shown by p-PPARγ/PPARγ ratio and Runx2 levels, although BMPR-IA level was significantly higher in osteoporotic than in control MSCs. In addition, staining for p-Smad-1/5/8 in o-MSCs was observed around nuclei at all experimental conditions. Taken together results demonstrate failure of BMP-2 signaling in osteoporotic MSCs. J. Cell. Biochem. 116: 1267-1277, 2015.