AbstractGiant‐cell tumor is a primary bone tumor, of uncertain origin, with the potential capacity to metastasize. To study the role of c‐mycand c‐fosoncogene overexpression in the tumorigenesis and metastatic spread of giant‐cell tumors. 32 primary tumors were collected: of these. 19 remained disease‐free and 13 metastasized to the lung. Samples of lung metastasis from these 13 patients were also available for study. The expression of c‐mycand c‐fosmRNA was studied by reverse transcription‐polymerase chain reaction and byin situhybridization. The expression of protein was studied by Western blot analysis and by immunohistochemistry. C‐mycmRNA was overexpressed in 12 (38%) of the 32 primary tumors. Thirteen primary tumors metastasized to the lung: in nine (69%) of these. c‐mycmRNA was overexpressed. The c‐mycprotein was overexpressed in seven (54%) of the 13 tumors that metastasized to the lung. C‐foswas overexpressed in only one lung metastasis. A strong correlation between the overexpression of c‐mycand the occurrence of metastases was found: thus, c‐mycseems a powerful prognosticator in giant‐cell tumor. C‐mycwas overexpressed both in giant cells and in mononuclear cells, suggesting that both cell types are involved i