Papillary thyroid carcinoma (PTC) is a well-differentiated endocrine malignant tumor that develops from thyroid follicular epithelium. The tumor represents the most common type of endocrine malignancy; however, its tumorigenesis is not fully elucidated. The aim of this study was to address the functional role of the sorting nexin (SNX) family in PTC because of recent experimental evidence suggesting that the SNX family members actively control endocytotic transportation as well as cell fate. Expression profiles of SNX family members of PTC showed a significant quantity of transcripts of SNX5. Further immunohistochemical analysis with an SNX5-specific monoclonal antibody established in this study consistently demonstrated the preferential expression of SNX5 in PTC (94.2%, 113/120 cases) as indicated by studies on 440 cases of various tumors. In contrast, other major carcinomas originating from the lung (2.6%, 1/38 cases), breast (5.1%, 2/39 cases), and intestine (4.2%, 1/24 cases) scarcely expressed SNX5. When we investigated models of murine thyroid tumors induced by the administration of carcinogens, high expression of Snx5 was also observed in well-differentiated thyroid tumors, further implying that the tumorigenesis of the thyroid gland was tightly associated with the abundance of SNX5/Snx5. Moreover epithelial cells expressing excess SNX5 showed high levels of Caspase-2 of an initiator caspase. Collectively these findings suggest that the evaluation of SNX5 expression would support pathological diagnosis of primary and secondary PTC. (Cancer Sci 2012; 103: 1356–1362)