The pathogenesis of osteogenic sarcoma is not known. Recently, chronic fluoride exposure has been incriminated as having a possible etiologic role by causing a nonspecific osteoblast proliferation. We were interested in exploring the possible relationship between fluoride bone content and p53 mutations. We analyzed p53 mutations in various exons in tissue of osteosarcoma, and correlated the findings with the bone fluoride levels in Indian patients. We analyzed tissue samples from 20 osteosarcoma patients for possible genetic alterations including mutations, and we assessed the extent of fluoride accumulation in bone. Fragments displaying an altered electrophoretic mobility were confirmed as having mutated sequences. Mutation was observed in samples of two cases (10% incidence). Eighteen samples showed bone fluoride levels between 1000 and 27,000 ppm, whereas the 2 mutated samples showed fluoride levels of 64,000 and 89,000 ppm, respectively. The high levels of bone fluoride levels and the similarity of the mechanisms of action between fluoride-induced DNA damage and chemically-induced p53 mutations lead us to propose that high fluoride bone content might have been one of the major factors causing osteosarcoma.