The Fas-FasL system seems to mediate thyrocyte death in Hashimoto's thyroiditis. In thyroid cancer, down-regulation of bcl-2 seems to alter apoptosis control. We compared the expression of immunoreactive Fas and FasL in normal thyroid with that of tumors ranging from benign to highly aggressive. Fas is essentially not expressed in normal thyrocytes, whereas FasL is expressed in approximately one-third of cases. Expression of both markers is significantly up-regulated in adenoma and in well-differentiated papillary and follicular carcinoma. In contrast, Fas is suppressed and FasL is strongly reduced in the most aggressive histological variants (poorly differentiated and undifferentiated carcinoma). Immunohistochemistry findings have been confirmed by analysis of Fas-FasL mRNA transcripts. In vitro studies showed that the Fas receptor of thyroid tumor cells was functional, because apoptosis was induced by an agonistic Fas antibody. Fas-expressing and Fas-resistant mammary cell lines were used as specificity controls. Together with our previous data inversely relating bcl-2 expression and thyroid tumor grade, the present findings further indicate that apoptotic pathways are altered in thyroid neoplasia. Thus, the Fas-FasL system may represent a marker of tumor aggressiveness.