Mutations in the BRAF gene have recently been detected in a wide range of neoplastic lesions with a particularly high prevalence in melanoma and papillary thyroid carcinoma (PTC). The hot-spot mutation BRAFV599E is frequently detected in PTC (36–69%), in contrast to its absence in other benign or malignant thyroid lesions. In order to unravel whether there is any association between the occurrence of the BRAF mutation and the histological pattern of PTC, in this study a previous series of 50 PTCs was extended to 134 cases, including ten cases of PTC-related entities—hyalinizing trabecular tumour (HTT) and mucoepidermoid carcinoma (MEC). Using PCR/SSCP and sequencing, the BRAFV599E mutation was detected in 45 of the 124 PTCs (36%). No mutations were detected in any case of HTT and MEC. BRAFV599E was present in 75% of Warthin-like PTCs and 53% of conventional PTCs, whereas no BRAFV599E mutations were detected in any of the 32 cases of the follicular variant of PTC. BRAFV599E was also detected in 6 of 11 cases of the oncocytic variant of PTC that displayed a papillary or mixed follicular–papillary growth pattern and in none of the four oncocytic PTCs with a follicular growth pattern. A distinct mutation in BRAF (codon K600E) was detected in three cases of the follicular variant of PTC. This study has confirmed the high prevalence of BRAFV599E in PTC and has shown that the mutation is almost exclusively seen in PTC with a papillary or mixed follicular–papillary growth pattern, regardless of the cytological features of the neoplastic cells. The results support the existence of an oncocytic variant of PTC that should be separated from the oncocytic variant of follicular carcinoma and suggest that the follicular variant of PTC may be genetically different from conventional PTC. Copyright © 2004 John Wiley & Sons, Ltd.