The receptor for advanced glycation end‐products (RAGE)‐mediated cellular activation through the mitogen‐activated protein kinase (MAPK) cascade, activation of NF‐κB and Rho family small G‐proteins, cdc42/Rac, is implicated in the pathogenesis of inflammatory disorders and tumor growth/metastasis. However, the precise molecular mechanisms for the initiation of cell signaling by RAGE remain to be elucidated. In this study, proteins which directly bind to the cytoplasmic C‐terminus of RAGE were purified from rat lung extracts using an affinity chromatography technique and identified to be extracellular signal‐regulated protein kinase‐1 and ‐2 (ERK‐1/2). Their interactions were confirmed by immunoprecipitation of ERK‐1/2 from RAGE‐expressing HT1080 cell extracts with anti‐RAGE antibody. Furthermore, the augmentation of kinase activity of RAGE‐bound ERK upon the stimulation of cells with amphoterin was demonstrated by determining the phosphorylation level of myelin basic protein, an ERK substrate. In vitro binding studies using a series of C‐terminal deletion mutants of human RAGE revealed the importance of the membrane‐proximal cytoplasmic region of RAGE for the direct ERK–RAGE interaction. This region contained a sequence similar to the D‐domain, a ERK docking site which is conserved in some ERK substrates including MAPK‐interacting kinase‐1/2, mitogen‐ and stress‐activated protein kinase‐1, and ribosomal S6 kinase. These data suggest that ERK may play a role in RAGE signaling through direct interaction with RAGE.