Objective: Ethyl Pyruvate (EP) has been shown to be an effective anti-inflammatory agent in a variety of model systems. The aim of this study was to investigate the effects of EP on High Mobility Group Box1 (HMGB1) genes expression and the possible mechanisms of EP protecting against acute lung injury induced by sepsis. Methods: Forty Wistar rats were randomly divided into normal controls, sham operation, acute lung injury, and EP treatment (40 mg/kg intra-peritoneally every 6 hrs ) groups. At the time points of 24 hours the animals in each group were sacrificed, and the lungs were harvested. Wet/dry lung weight ratio, the protein in the bronchoalveolar lavage fluid(BALF), and pulmonary permeability index(PPI) were determined. The histological morphology of lung was observed under microscope. The expression of HMGB1 mRNA was measured using semi-quantitative RT-PCR. Results: EP treatment decreased wet/dry lung weight ratio, the protein in the BALF, and PPI ( P ＜ 0.01 ). The histological morphology of lung injury was ameliorated. EP significantly inhibited the HMGB1 mRNA expression (P ＜ 0.01 ). HMGB1 mRNA expression in lungs positivelycorrelation with wet/dry lung weight ratio, the protein in the BALF, and PPI. Conclusion: EP administered inhibits HMGB1 mRNAexpression, and protects the lungs against acute injury induced by sepsis.