Langerin is a type II transmembrane C-type lectin associated with the formation of Birbeck granules in Langerhans cells. Langerin is a highly selective marker for Langerhans cells and the lesional cells of Langerhans cell histiocytosis. Although Langerin protein expression in Langerhans cell histiocytosis has been previously documented, the specificity of Langerin expression as determined by immunohistochemistry in the context of other histiocytic disorders has not been well established. In the present study, Langerin immunoreactivity was examined in a series of histiocytic disorders of monocyte/macrophage and dendritic cell derivation to assess the specificity and utility of Langerin as a diagnostic marker for Langerhans cell histiocytosis. Immunohistochemical expression of CD1a was also evaluated for comparison. Seventeen cases of Langerhans cell histiocytosis and 64 cases of non-Langerhans cell histiocytic disorders were examined. Langerin and CD1a were uniformly expressed in all cases of Langerhans cell histiocytosis, with the exception of one case that was positive for Langerin and negative for CD1a. Among the non-Langerhans cell histiocytic disorders evaluated, focal Langerin immunoreactivity was observed only in 2 of 10 cases of histiocytic sarcoma. All non-Langerhans cell histiocytic disorders showed no expression of CD1a. Langerin expression seems to be a highly sensitive and relatively specific marker of Langerhans cell histiocytosis. Immunohistochemical evaluation of Langerin expression may have utility in substantiating a diagnosis of Langerhans cell histiocytosis and separating this disorder from other non-Langerhans cell histiocytic proliferations.