The nature of fibrous dysplasia, a well-known and relatively common bone lesion, is controversial. We report here the first polymerase chain reaction (PCR)-based clonality analysis of fibrous dysplasia in which 11 cases obtained from females with a polymorphism at the human androgen receptor gene locus ( HUMARA) were examined using a methylation-specific PCR procedure. This assay allowed accurate evaluation of the clonality status of this disease by eliminating restriction enzyme digestion that had been used previously in conventional HUMARA analysis. Eight samples proved to be informative for the assay, and they all showed non-random X-chromosome inactivation, indicative of a monoclonal pattern. These findings demonstrate a clonal origin for fibrous dysplasia, suggesting that the disease is a neoplastic lesion rather than a "dysplastic" process, as has been generally believed.