Chondroblastoma (CBL) is a benign neoplasm of bone for which the genomic characteristics remain unclear. We compared the status of allelic losses of CBL with that seen in a set of chondrosarcomas (CS) to determine whether differences in their natural history and behavior are also reflected genetically. Eleven cases of CBL and 10 cases of CS of different grades were included. Tumors were subjected to microdissection and polymerase chain reaction using 17 markers located near genes on chromosomes 5, 9, 11, 13, 17, and 19. The selected chromosomes are known to be involved in several mesenchymal neoplasms. Fluorescence in situ hybridization was also performed on tumors displaying allelic losses, with dual-color probes for 9p, 17p, and 13q. Fractional allelic losses per gene ranged from 18.2% to 63.7% in CBLs and from 28.6% to 66.7% in CSs. Loss of heterozygosity (LOH) of 5q, 9p, 11p, 13q, and 19q occurred in both CBLs and CSs. Loss of heterozygosity of 17p (p53 locus) occurred in 7 of 11 CBLs and in only 1 case of recurrent CS. The pattern of allelic loss was similar in low-grade CSs and CBLs. Loci with LOH in both tumor types suggest possible involvement of the genes p53, RB1, CDKN2/p16, ERC, and XRCC in tumorigenesis. Overall correlation between LOH and fluorescence in situ hybridization results was 90% with 17p13, 80% with 9p, and 60% with 13q. The role of p53 in CBL is uncertain; however, given the benign behavior of this tumor, it is probably unrelated to tumor progression.