Medullary thyroid carcinoma (MTC) is an uncommon tumour of calcitonin-secreting C-cells of the thyroid gland. This cancer represents an important potential model for the study of mechanisms of human epithelial cell transformation. Although recent studies have identified the gene involved in familial forms of MTC, little is known about the molecular pathogenesis of the sporadic variants of this tumour. The biological and prognostic significance of TFF1 expression, particularly in diverse human malignancies, suggests that the TFF1 protein could have a role in human neoplasia. Furthermore, in prostate cancer it has been demonstrated that TFF1 expression is closely associated with premalignant changes and neuroendocrine differentiation. In the present study, the expression of TFF1 was analysed in 18 human MTCs, comprising sporadic and familial tumours, C-cell hyperplasia, and one case of lymph gland metastasis. TFF1 expression was also examined in the cultures of a human MTC-derived tumour cell line (TT cell line). The results showed that ten sporadic tumours, three hereditary tumours (including C-cell hyperplasia), and one lymph gland metastasis displayed TFF1 immunoreactivity. Indirect fluorescence immunocytochemistry and Western blotting revealed that the TFF1 protein was strongly expressed in the TT cells. Northern analysis revealed that tumours and TT cells expressed the TFF1 transcript. Although the function of TFF1 protein in the carcinogenesis of MTC remains to be elucidated, its expression in the majority of cases of both sporadic and hereditary tumours, metastatic tumours, and in C-cell hyperplasia suggests that it may contribute to the pathogenesis of MTC.