The soy isoflavone genistein is a phytochemical which can affect the proliferation of both normal and cancer cells. The specific inhibition of protein tyrosine kinase (PTK) by which it effects the proliferation of cancer cells is a well-known mechanism of its action. Glycosaminoglycans (GAGs)/proteoglycans (PGs) are considered to be of great importance in the development and progression of cancer. The synthesis of GAGs by two osteosarcoma cell lines, MG-63 and SAOS-2, which differ in the density of estrogen receptors (ER) they express, and the effects of genistein on their synthesis and distribution among culture medium and cell membrane were studied. The obtained results showed that both cell lines synthesized extracellular hyaluronan (HA) and both extracellular and cell-associated galactosaminoglycans (GalAGs) and heparan sulfate (HS). Even though both cell lines synthesized considerable amounts of PGs, the SAOS-2 cells produced HA, GalAGs and HS at considerably lower rates than the MG-63 cells. The inhibitory effect of genistein on the synthesis of both extracellularly secreted and cell-associated GAGs/PGs in SAOS-2 2 cells was found to be dose-dependent and mediated most probably by a PTK mechanism. The synthesis of GAGs/PGs by the MG-63 cells in the presence of genistein was dependent on their type and localization, suggesting that a more complex mechanism regulates the PG synthesis. This may well involve the effect of genistein via the estrogen receptors, which are present in much higher density in MG-63 cells as compared to SAOS-2 cells.