Hyalinizing trabecular tumour (HTT) of the thyroid is a neoplasm of follicular derivation that shares several morphological similarities with papillary thyroid carcinoma (PTC). In this study, we investigated the prevalence of B-raf point mutations, RET/PTC rearrangements and N-ras point mutations in a large HTT series (28 samples). Twenty benign thyroid lesions and 10 PTC served as control cases. A high (47%) prevalence of RET/PTC rearrangements was found in HTT. By contrast, neither B-raf nor N-ras mutations were found in HTT. These findings suggest that, although RET/PTC, N-ras, and B-raf proteins may act along the same signalling cascade, the biological and morphological outcome of their oncogenic activation is not completely overlapping. Thus, in clinical practice, the detection of B-raf mutations in a thyroid follicular tumour may prove to be a valuable tool, supplementing histological examination, and allowing a differential diagnosis between PTC and HTT.