Cytogenetic studies of mesenchymal chondrosarcoma are few and to date, no specific or recurrent aberrations have been found. In this investigation, the cytogenetic and molecular cytogenetic (spectral karyotypic and fluorescence in situ hybridization) findings for two mesenchymal chondrosarcomas, one arising skeletally and the other extraskeletally, are reported. An identical Robertsonian translocation involving chromosomes 13 and 21 [der(13;21)(q10;q10)] was detected in both cases, possibly representing a characteristic rearrangement for this histopathologic entity. Both cases also exhibited loss of all or a portion of chromosomes 8 and 20 and gain of all or a portion of chromosome 12. The observation of similar chromosomal abnormalities in both skeletal and extraskeletal mesenchymal chondrosarcoma supports a genetic as well as histopathologic relationship between these anatomically distinct neoplasms.