Objective To investigate changes in high mobility group box-1 protein ( HMGB1 ) level in brain tissues with severe sepsis, and the relationship between HMGB1 and septic brain injury.Methods Forty wild C57BL/6 mice were randomly ( random number) divided into 4 groups: sham group, sepsis group, cerebroventricular injection control group, and sepsis with BoxA ( HMGB1 inhibitor) cerebroventricular injection group.Septic model was reproduced by cecal ligation and puncture, and the cerebroventricular catheterization model was established by motorized mice brain stereotaxic instruments.After septic challenge, 1 μg BoxA was injected into the ventricle of brain via cerebroventricular catheter immediately.Mice were sacrificed and brains were harvested at 24 h after sepsis, and hippocampus tissue was separated immediately.Expressions of brain HMGB1 and caspase-3 changed in apoptotic neurons and brain injury were determined by brain tissue immunofluorescence, Western blotting, TUNEL and HE staining respectively.One-way analysis of variance ( ANOVA) for analyzing inter-group differences, student t test for comparing difference between two groups . Results (1) HMGB1 expression in hippocampus was significantly enhanced in the septic group compared to the sham group [ (22.74 ±9.29) vs.4.57 ±2.18, P<0.01].(2) Compared to the sham group, neuronal apoptosis [ (35 ±9.17) vs.(1.67 ±1.53) , P<0.01) and caspase-3 expressions [ (16.79 ±8.17) vs.( 3.39 ±2.09), P<0.05] were significantly increased in hippocampus with aggravated brain injury in the septic group.(3) Cerebroventricular injection of BoxA significantly inhibited HMGB1 in hippocampus [ (2.66 ± 2.06) vs.( 22.74 ±9.29), P<0.01];(4) Cerebroventricular injection of BoxA obviously alleviated acute brain injury, and decreased neuronal apoptosis [ ( 12 ±4.36 ) vs.( 35 ±9.17 ) , P <0.01 ] as well as caspase-3 activity [ (4.10 ±2.11) vs.(16.80 ±8.17), P<0.05].Conclusions The elevated expression of brain HMGB1 is closely related to pathogenesis and development of septic brain injury, and treatment with antagonist towards brain HMGB1 can markedly attenuate acute brain injury following severe sepsis.