The BRAF V600E mutation has been identified in a high proportion of papillary thyroid carcinoma (PTC). In cell lines and a transgenic mouse model it has been demonstrated that the mutation constitutively activates the mitogen-activated protein kinase (MAPK) pathway but in human PTC samples its effects remain unexamined. Herein the correlation of BRAF mutation and MAPK activation was examined in 42 human PTC samples. Activating mutations of the BRAF gene and all three RAS genes were detected by polymerase chain reaction-direct sequencing, and RET/PTC1 rearrangements were screened by nested reverse transcription-polymerase chain reaction. MAPK activation was assessed by immunohistochemistry and western blot analysis. Twenty-eight cases (66.7%) of BRAF V600E mutation, three cases (7.1%) of RET/PTC1 rearrangement but no cases of RAS genes mutation were identified. Activated MAPK was found in six cases (14.3%) with only two cases of mutant BRAF. In total 7.1% of PTC with BRAF mutation had activated MAPK. Furthermore, BRAF mutations were more prevalent in patients > or =45 years, but did not correlate with aggressive clinical behaviors. Absence of association between BRAF mutation and activation of MAPK pathway in PTC suggests the presence of mechanisms that downregulate MAPK activation.