Objective: To investigate the mechanism of high mobility of protein B1 (HMGB1) in promoting migration and proliferation of vascular smooth muscle cells (VSMCs). Methods: The changes in migration and proliferation ability as well as the expressions of receptor for advanced glycation end-products (RAGE) and P38MAPK were measured in human aortic VSMCs (HA-VSMCs) after exposure to HMGB1. Further, the influence of RAGE antibody or P38MAPK inhibitor SB203580 pretreatment was observed. Results: After exposure to HMGB1, the activity of the cell proliferation and migration, as well as the expression of RAGE and P38MAPK were increased significantly (all P<0.05), and all presented in a concentration-dependent manner. The promoting effects of HMGB1 on migration and proliferation ability were significantly inhibited by either RAGE antibody or SB203580 pretreatment (all P<0.05), and HMGB1-induced P38MAPK expression was significantly inhibited by RAGE antibody pretreatment (P<0.05). Conclusion: HMGB1 can probably promote the migration and proliferation of VSMCs through its binding to cell surface RAGE and then activating P38MAPK expression.