Giant cell-rich lesions of bone, including giant cell tumor of bone, giant cell reparative granuloma (GCRG), and aneurysmal bone cyst (ABC), may have overlapping clinical, radiologic, and histopathologic features. In fact, GCRG and solid ABC are currently differentiated solely based on skeletal location. Prior cytogenetic studies have reported that telomeric associations are present in the majority of giant cell tumors of bone, whereas translocations involving 16q22 and/or 17p13 are characteristic of ABCs. There is only one previously published karyotype of a GCRG, which revealed a reciprocal translocation, t(X;4)(q22;q31.3). We report 3 cases of giant cell-rich bone lesions with novel karyotypes: one lesion located in the first metacarpal, a typical location for GCRG, was histologically consistent with a giant cell tumor and showed the following karyotype [46,XX,inv(2)(p13q21),t(inv2;11)(q21;q13)]; the second lesion, also a giant cell tumor of bone, in the sacrum showed the following karyotype [46,XX,r(9)(p24q34)[cp7]/46,idem,?r(16)(p13.3q24)[cp10]/46,XX]. The third lesion, a hard palate mass, had the histopathologic features of a GCRG and a karyotype showing a reciprocal translocation, 46,XY,t(2;10)(q23;q24). These findings suggest that at least a subset of GCRGs may be neoplastic and that these lesions differ cytogenetically from classic giant cell tumors of bone or solid ABC, although the latter entity is otherwise indistinguishable from reparative granuloma. Further cytogenetic characterization of giant cell-rich bone lesions may improve the utility of karyotyping as a tool in their differential diagnosis and may shed light on the pathogenetic relationship between these lesions.