Several studies have shown that giant cell tumor of bone frequently exhibits telomeric associations, commonly at chromosome 11p, which is also the location of the H-ras oncogene. In addition, rare H-ras alleles are more common among cancer patients than among healthy controls and point mutations of this oncogene have also been reported in several malignancies. These data led us to investigate gene dosage, restriction fragment-length size, and point mutations for H-ras in giant cell tumor of bone. Quantitative Southern blot analysis revealed no amplification of the H-ras oncogene in tumor DNA compared with DNA from peripheral blood in the same patient or from control subjects. In addition, no point mutations were detected in codons 12, 13, or 61 (mutations of these codons have been reported in other neoplasms) of the H-ras gene. No differences were noted in restriction fragment-length polymorphisms between tumor and peripheral blood in the same patient and no loss of heterozygosity was detected. In addition, there was no increased frequency of rare H-ras alleles (8% of alleles) in giant cell tumor patients compared to controls (21% of alleles) in our study. However, large allele sizes (> 8.5 kb) were significantly overrepresented in GCT patients compared with healthy controls. In our study, three of 12 alleles were found to be rare in the healthy controls but were common among GCT patients. Our data suggest that the H-ras oncogene is unlikely to be the site of a biologically significant primary lesion in GCT tumorigenesis.