Forty-seven cases of giant cell tumor (GCT) of bone were reviewed pathologically to elucidate the origin of spindle-shaped stromal cells or the histogenesis of mononuclear histiocytic stromal cells and osteoclast-like giant cells (OCGC). To clarify the histogenesis of OCGC, eight cases of sarcoma associated with OCGC were reviewed for a comparative study. Spindle-shaped stromal cells sometimes produced minute focl of osteoid matrix. Proliferating cell nuclear antigen (PCNA) was observed in spindle-shaped stromal cells and mononuclear histiocytic stromal cells, but not in OCGC. Matrix metalloproteinase (MMP)-9 was expressed by mononuclear histiocytic stromal cells and OCGC, and its expression was correlated with the lung metastasis rate. In both GCT and sarcomas with OCGC, mononuclear histiocytic stromal cells and OCGC expressed CD68, parathyroid hormone-like protein (PTH-LP), MMP-1 and MMP-9. Immunoreactivity of mononuclear histiocytic stromal cells and OCGC to CD68, PTH-LP, MMP-1 and MMP-9 was similar between GCT and sarcomas with OCGC. These observations may suggest that mononuclear histiocytic stromal cells and OCGC are reactively induced with several cytokines acting in an autocrine or paracrine fashion and that these cells are closely related with the biologic aggressiveness of GCT.