Mesenchymal stromal cells (MSC) are multipotent cells that can be differentiated in vitro into a variety of cell types, including adipocytes or osteoblasts. Our recent studies indicated that a high expression of CD146 on MSC from bone marrow correlates with their robust osteogenic differentiation potential. We therefore investigated if expression of CD146 on MSC from placenta correlates with a similar osteogenic differentiation potential. The MSC were isolated specifically from the endometrial and fetal parts of human term placenta and expanded in separate cultures, and compared to MSC from bone marrow as controls. The expression of cell surface antigens was investigated by flow cytometry. Differentiation of MSC was documented by cytochemistry and analysis of typical lineage marker genes. CD146 positive MSC were separated from CD146 negative cells by magnet-assisted cell sorts (MACS). We report that the expression of CD146 is associated with a higher osteogenic differentiation potential in human placenta-derived MSC (pMSC) and the CD146pos pMSC generated a mineralized extracellular matrix, whereas the CD146neg pMSC failed to do so. In contrast, adipogenic and chondrogenic differentiation of pMSC were not different in CD146pos compared to CD146neg pMSC. Upon enrichment of pMSC by MACS the CD146neg and CD146pos populations maintained their expression levels for this antigen for several passages in vitro. We conclude that CD146pos pMSC either respond to osteogenic stimuli more vividly or, alternatively, CD146pos present a pMSC subset that is pre-determined to differentiate into osteoblasts.