Calcifying epithelial odontogenic tumors (CEOTs), also known as Pindborg tumors, are characterized by the presence of squamous-cell proliferation, calcification, and, notably, amyloid deposits. On the basis of immunohistochemical analyses, the amyloidogenic component had heretofore been deemed to consist of cytokeratin-related or other molecules; however, its chemical composition had never been elucidated. We have used our microanalytic techniques to characterize the protein nature of CEOT-associated amyloid isolated from specimens obtained from 3 patients. As evidenced by the results of amino-acid sequencing and mass spectrometry, the fibrils were found to be composed of a polypeptide of approximately 46 mer. This component was identical in sequence to the N-terminal portion of a hypothetical 153-residue protein encoded by the FLJ20513 gene cloned from the human KATO III cell line. That the amyloid protein was derived from this larger molecule was demonstrated by reverse transcription-polymerase chain reaction amplification of tumor-cell RNA where a full-length FLJ20513 transcript was found. Furthermore, immunohistochemical analyses revealed that the amyloid within the CEOTs immunostained with antibodies prepared against a synthetic FLJ20513-related dodecapeptide. Our studies provide unequivocal evidence that CEOT-associated amyloid consists of a unique and previously undescribed protein that we provisionally designate APin.