The pathogenesis of pulmonary fibrosis remains unclear. The receptor for advanced glycation end products (RAGE) is a multi-ligand receptor known to be involved in the process of fibrotic change in several organs, such as peritoneal fibrosis and kidney fibrosis. The aim of this study was to examine the contribution of RAGE during the acute inflammation and chronic fibrotic phases of lung injury induced by intratracheal instillation of bleomycin in mice. Bleomycin-induced lung fibrosis was evaluated in wild-type and RAGE-deficient (RAGE-/-) mice. Bleomycin administration to wild-type mice caused an initial pneumonitis that evolved into fibrosis. While RAGE-/- mice developed a similar early inflammatory response, the mice were largely protected from the late fibrotic effects of bleomycin. The protection afforded by RAGE deficiency was accompanied by reduced pulmonary levels of potent RAGE-inducible pro-fibrotic cytokines transforming growth factor (TGF) and PDGF. In addition, bleomycin administration induced HMGB-1 production, one of the ligands of RAGE, from inflammatory cells that accumulated within the airspace. Co-culture with HMGB-1 induced epithelial-mesenchymal transition (EMT) in alveolar type II epithelial cells from wild-type mice. However, alveolar type II epithelial cells derived from RAGE-/- mice did not respond to HMGB-1 treatment, such that the RAGE/HMGB-1 axis may play an important role in EMT. Also, bleomycin administration induced pro-fibrotic cytokines, TGF- and PDGF, only in wild-type mouse lungs. Our results suggested that RAGE contributes to bleomycin-induced lung fibrosis through EMT and pro-fibrotic cytokine production. Thus, RAGE may be a new therapeutic target for pulmonary fibrosis.