Langerhans cell histiocytosis (LCH) is a neoplastic disorder that results in clonal proliferation of cells with a Langerhans cell (LC) phenotype. The pathogenesis of LCH is still poorly understood. In the present study, serial analysis of gene expression (SAGE) was applied to LCs generated from umbilical cord blood CD34+ progenitor cells to identify LC-specific genes and the expression of these genes in LCH was investigated. Besides the expression of several genes known to be highly expressed in LCs and LCH such asCD1a, LYZ, andCD207, high expression of genes not previously reported to be expressed in LCs, such asGSN, MMP12, CCL17, andCCL22, was also identified. Further analysis of these genes by quantitative RT-PCR revealed high expression ofFSCN1andGSNin all 12 LCH cases analysed; ofCD207, MMP12, CCL22, andCD1ain the majority of these cases; andCCL17in three of the 12 cases. Immunohistochemistry confirmed protein expression in the majority of cases. The expression ofMMP12was most abundant in multi-system LCH, which is the LCH type with the worst prognosis. This suggests that expression ofMMP12may play a role in the progression of LCH. These data reveal new insight into the pathology of LCH and provide new starting points for further investigation of this clonal proliferative disorder. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.