Extracellular newly identified RAGE-binding protein (EN-RAGE) is a ligand of the receptor for advanced glycation endproducts (RAGE) and has been termed S100A12. The ligation of EN-RAGE with RAGE on the endothelium, mononuclear phagocytes and lymphocytes triggers cellular activation with the generation of the key proinflammatory mediators interleukin (IL)-1beta and tumour necrosis factor (TNF)-alpha.The aim of this study was to investigate the presence of RAGE and EN-RAGE, their spatial localization and their coexpression in leprosy lesions.Immunohistochemistry and confocal laser scanning microscopy were used to evaluate the expression of RAGE and EN-RAGE in leprosy. By enzyme-linked immunosorbent assay, RAGE and EN-RAGE were detected in the serum.(1) In the multibacillary (MB) and paucibacillary (PB) groups, the level of RAGE production was significantly higher than in patients with atypical mycobacterial infection or sarcoidosis (P < 0.01). In the MB group, the production of RAGE was higher than in the PB group (P < 0.01), and it was higher in patients without the lepra reaction than in patients with the lepra reaction (P < 0.05). (2) In MB, PB and atypical mycobacterial infection, the level of EN-RAGE production was significantly higher than in sarcoidosis (P < 0.01). (3) In the confocal laser scanning microscopic examination, the RAGE and EN-RAGE proteins were detected in lepromatous leprosy. These proteins are spatially colocalized along the cell surface, which is in agreement with their receptor-ligand interaction. (4) A comparable amount of EN-RAGE was detected in the serum of the MB and PB groups. Patients with the reaction showed a higher level of EN-RAGE than patients without the reaction in leprosy.Our data suggest that in leprosy, RAGE and EN-RAGE may be involved in the proinflammatory process rather than the antimycobacterial activity, especially during the lepra reaction. The blockade of the interaction of RAGE and EN-RAGE at the early stage of the inflammatory process may minimize the inflammatory response and consequent tissue damage or the sequelae of leprosy.