The effect of bone marrow mesenchymal stem cells (BMSCs) in treatment for multiple organ dysfunction syndrome (MODS)remains unknown and the mechanism is still unclear. Therefore, the goal of this study is to investigate the effects of intracellularhigh mobility group box 1 protein (HMGB1) on BMSCs treating for MODS. The rats were given 15% blood loss plus 1 mg/kglipopolysaccharide (LPS) via lower extremity superficial venous, then randomly allocated into four groups: sham group, MODSgroup, MODS plus BMSC group, MODS plus ethyl pyruvate (EP) group, MODS plus BMSCs plus EP group. Twenty-fourhours later, rats in groups were sacrificed and then the blood and tissues were collected to evaluate the changes of tissuehistopathology, cell apoptosis, inflammation level and organ function. The HGMB1 expression was monitored by RT-qPCRand Western blot. The expression of RAGE/TLR2/TLR4 and NF-κB at the protein levels was also assessed. BMSCs and/or EPexhibitsanoutstandingprotectiveeffectagainstLPS-inducedhistopathologicalinjurybyimprovingcellapoptosis,inflammatoryresponse and the organ dysfunction but no effect on BMSC homing to the injury site. Moreover, BMSCs and/or EP inhibitedLPS-induced upregulation of HMGB1, RAGE, TLR2 and TLR4 expression at protein levels and compromised p65 phosphor-ylation in the rat model of MODS. These findings suggest that HMGB1 is involved in BMSC treatment for MODS, throughregulation of the TLR2, TLR4-mediated NF-κB signal pathway. It suggests that HMGB1 is an attractive potential target for thedevelopment of new therapeutic strategies for MODS.