Some primary malignant or benign tumours of bone contain numerous multinucleated cells. These "giant cell-rich tumours of bone" have overlapping features and clinical and radiological data are needed to reach an accurate pathological diagnosis. We studied the potential contribution of p63 immunohistochemistry to the reliability of the histological diagnosis. We performed a multicentric retrospective study of 291 giant cell-rich tumours of bone which included 119 giant cell tumours of bone (GCTB), 76 aneurysmal bone cysts (ABC), 49 chondroblastomas (CB), 15 nonossifying fibromas (NOF), 10 giant cell reparative granulomas (RG) of jaws, 1 giant cell lesion of small bones, 2 hyperparathyroidism-related brown tumours (BT), 17 bone sarcomas with numerous osteoclasts and 2 malignant giant cell tumours of bone. p63 is expressed in ABC, CB, NOF, RG, BT and GCTB, but its expression in more than 50 % of mononuclear cells is strongly suggestive of a diagnosis of GCTB. In contrast, malignant GCTB were mostly negative. Our results show that p63 is expressed in a broad range of benign giant cell-rich tumours of bone, consistent with data in the recent literature, while infrequent in malignant tumours. With a cut-off 50 %, the presence of p63 positive cells is useful in supporting a diagnosis of giant cell-rich tumour of bone. However, a final diagnosis cannot be made without due consideration of all clinical/radiological and pathological data.