Dedifferentiated chondrosarcomas, which are known for their poor prognosis, are characterized by conventional chondrosarcoma with high-grade anaplastic components. Activating mutations in ras genes are a common genetic abnormality in human malignancies. The presence of point mutations at codons 12 and 13 of the H-ras gene was studied in 20 formalin-fixed paraffin-embedded chondrosarcomas, comprising 11 cases of conventional chondrosarcoma (six Grade 1 cases and five Grade 2 cases) and nine cases of dedifferentiated chondrosarcoma, using polymerase chain reaction-restriction fragment length polymorphism and direct sequencing analysis. H-ras mutations were only seen in two out of the nine cases of dedifferentiated chondrosarcoma (2/9, 22%) and they were not seen in any of the cases of conventional chondrosarcoma (0/11, 0%). Dedifferentiated chondrosarcomas had a worse prognosis than conventional chondrosarcomas (P < .01); among the patients with dedifferentiated chondrosarcomas, those with H-ras mutation (n = 2) tended to have a worse prognosis than those without (n = 7), although the difference was not statistically significant (P = 0.068). Our results would seem to suggest that H-ras mutation may occur during the course of dedifferentiation and may also have some effect on malignant potential.