Giant-cell tumor is a primary bone tumor, of uncertain origin, with the potential capacity to metastasize. To study the role of c-myc and c-fos oncogene 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-myc and c-fos mRNA was studied by reverse transcription-polymerase chain reaction and by in situ hybridization. The expression of protein was studied by Western blot analysis and by immunohistochemistry. C-myc mRNA was overexpressed in 12 (38%) of the 32 primary tumors. Thirteen primary tumors metastasized to the lung; in nine (69%) of these, c-myc mRNA was overexpressed. The c-myc protein was overexpressed in seven (54%) of the 13 tumors that metastasized to the lung. C-fos was overexpressed in only one lung metastasis. A strong correlation between the overexpression of c-myc, and the occurrence of metastases was found: thus, c-myc seems a powerful prognosticator in giant-cell tumor. C-myc was overexpressed both in giant cells and in mononuclear cells, suggesting that both cell types are involved in the progression of this tumor.