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Context: There are several genetic and molecular evidences suggesting dysregulation of the mammalian target of rapamycin (mTOR) pathway in thyroid neoplasia. Activation of the phosphatidylinositol- 3-kinase/AKT pathway by RET/PTC and mutant RAS has already been demonstrated, but no data have been reported for the BRAF^V600E mutation. Objective: The aim of this study was to evaluate the activation pattern of the mTOR pathway in malignant thyroid lesions and whether itmaybe correlated withknowngenetic alterations, as well as to explore the mechanisms underlying mTOR pathway activation in these neoplasias. Results: We observed, by immunohistochemical evaluation, an up-regulation/activation of the mTORpathway proteins in thyroid cancer, particularly in conventional papillary thyroid carcinoma (cPTC). Overactivation of the mTOR signaling was particularly evident in cPTC samples harboring the BRAF^V600E mutation. Transfection assays with BRAF expression vectors as well as BRAF knockdownby small interfering RNA revealed a positive association between BRAF expression andmTOR pathway activation, which appears to be mediated by pLKB1 Ser428, and emerged as a possible mechanism contributing to the association between BRAF mutation and mTOR pathway up-regulation. When we evaluated the rapamycin in the growth of thyroid cancer cell lines, we detected that cell lines with activating mutations in the MAPK pathway show a higher sensitivity to this drug. Conclusions: We determined that the AKT/mTOR pathway is particularly overactivated in human cPTC harboring the BRAF^V600E mutation. Moreover, our results suggest that the mTOR pathway could be a good target to enhance therapy effects in certain types of thyroid carcinoma, namely in those harboring the BRAF^V600E mutation. Copyright © 2012 by The Endocrine Society.