The key pathologic feature in Langerhans cell histiocytosis (LCH) is the presence of Birbeck granules in the tumor cells, which can be seen in electron microscopic examination. The diagnostic significance of this structure is unknown, because langerin is reported to be expressed in normal LCs in the epidermis. Langerin (CD207) is a type II transmembrane protein lectin associated with the formation of Birbeck granules in Langerhans cells (LCs). The aim of this study is to evaluate the sensitivity and specificity of langerin expression in LCH and other histiocytic disorders. S100 immunohistochemical expression was also evaluated for comparison. Eleven cases of LCH (one in lymph node, one in lung, and the others in bone), 3 cases of hemophagocytic lymphohistiocytosis (HLH), 1 cases of histiocytic sarcoma (lung), and 4 cases of reactive lymph nodes (LN) were examined. Among LCH, langerin was highly expressed in both bone and LN lesions, and comparable to S100 expression in the bone and LN lesions. Additionally, in LN LCH, langerin was also expressed in sinuses, where S100 was not expressed. In reactive LN langerin was also expressed in the paracortical and interfollicular cells, and subcapsular and medullary sinuses. In pulmonary LCH and histiocytic sarcoma, langerin was expressed only in LCs and low grade tumor cells of histiocytic sarcoma, but not in highly pleomorphic tumor cells. All 3 HLH were negative for langerin in the histiocytes. Langerin immunohistochemical staining was sensitive in all LCH lesions and specific in the bone and pulmonary lesions, but in the LN, it was simultaneously expressed in sinuses, paracortical and interfollicular cells in both LCH and reactive LN. So we should carefully interpret the result of langerin expression in the lesions of LN of LCH.