Piceatannol (3,3',4,5'-tetrahydroxy-trans-stilbene) is a polyphenol present in grapes and wine. By means of alkaline phosphatase activity and osteocalcin enzyme-linked immunosorbent assay (ELISA), we have shown that piceatannol exhibits a significant induction of differentiation in immortalized fetal osteoblasts (hFOB), and osteosarcoma cells (MG-63). Alkaline phosphatase and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively, our results indicate that piceatannol stimulate osteoblast differentiation at various stages (from maturation to terminally differentiated osteoblasts). Induction of differentiation by piceatannol was associated with increased bone morphogenetic protein-2 (BMP-2) production. Addition of purified BMP-2 protein did not increase the upregulation of alkaline phosphatase activity and osteocalcin secretion by piceatannol, whereas the BMP-2 antagonist noggin blocked piceatannol and BMP-2-mediated alkaline phosphatase activity, and osteocalcin secretion enhancement, indicating that BMP-2 production is required in piceatannol-mediated osteoblast maturation and differentiation. In conclusion, piceatannol increased BMP-2 synthesis, and this effect may contribute to its action on the induction of osteoblasts maturation and differentiation, followed by an increase of bone mass. Decreases in new bone formation, followed by estrogen deficiency or various pathologic factors, may contribute to the mechanisms involved in postmenopausal osteoporosis.