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Osteoclasts are marrow\u2010derived multinucleated cells that effect tumour osteolysis. The role of ES tumour cells in influencing osteoclast formation and\/or directly contributing to the osteolysis in ES has not been determined. Using a tissue culture bioassay, we found that lacunar resorption is not carried out by (CD99<jats:sup>+<\/jats:sup>) ES tumour cells, but by (CD68<jats:sup>+<\/jats:sup>) macrophage\/osteoclast\u2010like cells; this resorption occurred in the absence of the osteoclastogenic factor, receptor activator of nuclear factor \u03baB ligand (RANKL). ES cell lines cultured directly on dentine slices did not resorb the mineral or organic components of the bone matrix. Immunohistochemistry of ES tissue microarrays, western blotting, and RT\u2010PCR studies showed that ES cells strongly expressed both RANKL and macrophage\u2010colony stimulating factor (M\u2010CSF), two major osteoclastogenic factors. When co\u2010cultured with human monocytes, ES cells induced the formation of TRAP<jats:sup>+<\/jats:sup> osteoclastic cells. Conditioned medium from cultured ES cells did not result in osteoclast formation, indicating that cell\u2013cell contact is required for ES\u2010induced osteoclastogenesis. Our findings indicate that ES cells do not resorb bone directly but that they may support osteoclast formation by a RANKL\u2010dependent mechanism. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. 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