p63 expression in giant cell-containing lesions of bone and soft tissue. Previous studies have demonstrated p63 overexpression in giant cell tumors of bone and advocate its use as a potential diagnostic marker. Although routine histology is often all that is required to diagnose giant cell tumor of bone, immunohistochemistry could prove useful to distinguish it from other benign and malignant giant cell-containing lesions of bone and soft tissue on needle biopsies and unusual clinical settings.To assess p63 expression in giant cell-containing lesions of bone and soft tissue.p63 immunohistochemistry was performed in 23 giant cell tumors of bone, 8 primary aneurysmal bone cysts, 12 chondroblastomas, 4 giant cell reparative granulomas, 4 osteosarcomas, 15 tenosynovial giant cell tumors, 6 nonossifying fibromas, and 4 pigmented villonodular synovitides.p63 overexpression was identified in 20 of 23 giant cell tumors of bone (86.9%), 5 of 8 primary aneurysmal bone cysts (62.5%), 10 of 12 chondroblastomas (83.3%), 4 of 4 giant cell reparative granulomas (100%), 2 of 4 osteosarcomas (50%), 1 of 15 tenosynovial giant cell tumors (6.6%), 1 of 6 nonossifying fibromas (16.6%), and 1 of 4 pigmented villonodular synovitides (25%). The sensitivity, specificity, positive predictive value, and negative predictive value of p63 immunohistochemistry for the diagnosis of giant cell tumor of bone were 86.95%, 53.36%, 45.45%, and 91.17%, respectively.This study shows that although p63 is expressed by most giant cell tumors of bone, its lack of specificity limits its use as an immunohistochemical marker in the differential diagnosis of giant cell-containing lesions of bone and soft tissue.