AIMS: To compare the antigenic phenotype of giant cells in giant cell lesions of bone and soft tissue with that of osteoclasts and macrophage polykaryons. METHODS: Formalin fixed, paraffin wax embedded sections of 106 giant cell lesions, 19 granulomatous, and 14 osteoclast containing lesions were immuno-histochemically stained for leucocyte common antigen (LCA), CD68, and HLA-DR. RESULTS: Osteoclasts and giant cells of giant cell tumour of bone and giant cell reparative granuloma could be distinguished by their generalised absence of HLA-DR reaction from macrophage polykaryons and giant cells in other giant cell lesions of bone and soft tissue. Staining for LCA, CD68, and HLA-DR was useful in distinguishing reactive histiocytic giant cells and osteoclasts from tumour giant cells. CONCLUSIONS: A panel of macrophage associated antigens should be diagnostically useful in differentiating the histological nature of giant cells in various giant cell lesions of bone and soft tissue.