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Rearrangement of RET proto-oncogene is the major event in the etiopathogenesis of papillary thyroid carcinoma (PTC). We report a high prevalence of BRAF^V599E mutation in sporadic PTC and in PTC-derived cell lines. The BRAF^V599E mutation was detected in 23 of 50 PTC (46%) and in three of four PTC-derived cell lines. The prevalence of the BRAF^V599E mutation in PTC is the highest reported to date in human carcinomas, being only exceeded by melanoma. PTC with RET/PTC rearrangement as well as the TPC-1 cell line (the only one harboring RET/PTC rearrangement) did not show the BRAF^V599E mutation. BRAF^V599E mutation was not detected in any of 23 nodular goiters, 51 follicular adenomas and 18 follicular carcinomas. A distinct mutation in BRAF (codon K600E) was detected in a follicular adenoma. Activating mutations in RAS genes were detected in 15% of FA, 33% of FTC and 7% of PTC. BRAF^V599E mutation did not coexist with alterations in any of the RAS genes in any of the tumors. These results suggest that BRAF^V599E mutation is frequent in the etiopathogenesis of PTC. The BRAF^V599E mutation appears to be an alternative event to RET/PTC rearrangement rather than to RAS mutations, which are rare in PTC. BRAF^V599E may represent an alternative pathway to oncogenic MAPK activation in PTCs without RET/PTC activation.