Thyroid neoplasms show a wide variety of lesions varying from slowly growing differentiated adenocarcinomas to rapidly proliferating undifferentiated carcinomas. There has been some histopathological evidence that the undifferentiated thyroid carcinomas are derived from differentiated carcinomas. Moreover, it is suspected that some genetic events might be associated with such changes. In the present study, mutations in the p53 gene were investigated by direct sequencing analysis after polymerase chain reaction amplification of exons 5 to 8, using paraffin-embedded primary tumors and cultured cells. No mutations in exons 5 to 8 were detected in 10 differentiated papillary adenocarcinomas, whereas 6 of 7 undifferentiated carcinomas were found to carry base substitution mutations. Sequencing analysis confirmed mutations at codons 135 (TGC----TGT), 141 (CCC----CCT), 178 (CAC----GAC), 213 (CGA----TGA), 248 (CGG----CAG, CGG----TGG), and 273 (CGT----TGT). The spectrum of mutations (G:C to A:T transitions in 7 of 8) might be a specific feature of the spontaneous cancers. The results strongly suggest that, in human thyroid glands, p53 mutations play a crucial role in the progression of differentiated carcinomas to undifferentiated ones.