Background: High-mobility group box 1 (HMGB1), a ligand for receptor for advanced glycation end products (RAGE), is released from necrotic hepatocytes, and contribute to the pathogenesis of chronic hepatitis. T helper 17 cells (Th17) also have been suggested to participate in the pathogenesis of chronic hepatitis B (CHB) infection. We investigated the role of HMGB1-RAGE-Th17 axis in the pathogenesis of CHB. Methods: The levels of HMGB1 and IL-17 expression were detected by Western blotting and real-time RT-PCR in patients with CHB. The effect of HMGB1-RAGE on the immune activity of Th17 cells and vice versa, was assessed by an induction assay. The levels of IL-17 expression was determined by RT-PCR and Western blotting after blocking RAGE. Results: The levels of HMGB1 and IL-17 expression were higher in CHB patients than in controls. The levels of IL-17 were significantly elevated when PBMCs were stimulated with HMGB1 in vitro, and vice versa. The levels of IL-17 expression was significantly reduced when PBMCs were treated with competitors for RAGE in vitro. Conclusions: HMGB1-RAGE induces the generation of IL- 17, which mediates the pathogenesis of CHB infection. It is suggested that HMGB1 might be a potential target for controlling hepatitis B infection by suppressing Th17 activity.