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In this study, we have analysed the cytochemical and functional characteristics of mononuclear and multinucleated cells in PVNS and determined the cellular and humoral mechanisms underlying giant cell formation and resorption in PVNS. Giant cells and CD14<jats:sup>+<\/jats:sup> and CD14<jats:sup>\u2212<\/jats:sup> mononuclear cell populations were isolated from PVNS synovial tissue and cultured alone or in the presence and absence of the osteoclastogenic factors, RANKL and M\u2010CSF. Osteoclast formation and activity was assessed by expression of TRAP and evidence of lacunar resorption. Giant cells in PVNS expressed an osteoclast\u2010phenotype (CD51<jats:sup>+<\/jats:sup>, TRAP<jats:sup>+<\/jats:sup>, CD14<jats:sup>\u2212<\/jats:sup>, HLA\u2010DR<jats:sup>\u2212<\/jats:sup>) and were formed only in cultures of mononuclear cells that expressed the macrophage marker CD14. Osteoclast formation required RANKL and occurred in both the presence and absence of exogenous M\u2010CSF. CD14<jats:sup>\u2212<\/jats:sup> cells in PVNS expressed RANKL. Lacunar resorption by PVNS\u2010derived giant cells was abolished by the addition of the bisphosphonate, zoledronate. Our findings indicate that osteoclasts form by a RANKL\u2010dependent mechanism from CD14<jats:sup>+<\/jats:sup> mononuclear phagocytes in PVNS. Osteoclast formation occurred even in the absence of exogenous M\u2010CSF, a finding which is in keeping with over\u2010expression of M\u2010CSF playing a pathogenic role in this condition. Anti\u2010osteoclast resorptive treatment may be useful to control osteolysis in PVNS. Copyright \u00a9 2011 Pathological Society of Great Britain and Ireland. 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