Giant-cell bone tumors are considered to be benign proliferations composed of poorly differentiated mononuclear cells and large multinucleated giant cells with the appearance of osteoclasts. Treatment is usually surgical resection, but there is a small risk of local recurrence and metastasis. Cytogenetic analyses were performed on giant-cell bone tumors of six consecutive patients. Chromosomally abnormal clones were found in three of the tumors, but no two patients had the same chromosome abnormality. Thus, there was no correlation between any specific chromosome change and the clinical behavior or histology of giant-cell bone tumors. However, all of the tumors had a significantly higher incidence of nonclonal chromosome abnormalities than is encountered in cultures of normal cells. The most common nonclonal abnormalities involved unusual telomere-to-telomere chromosome translocations. These findings suggest that the cells in these tumors are chromosomally unstable. The telomeres most frequently involved were on the long arm of chromosomes 19 and 20.