Objective: To investigate the effect of mildronate(MIL) on the acute lung injury(ALI) induced by LPS in mice. Methods: According to the random number table,all 50 ICR mice were randomly divided into 5 groups,of which four groups was induced ALI and were respectively divided into LPS group,MIL 50 mg/kg group,MIL 100 mg/kg group,MIL 200 mg/kg group,each contains 10 mice. ICR mice was induced ALI by instilling intratracheally with 0.1ml LPS(2 mg/kg). Saline and mildronate (50,100 and 200 mg/kg) were injected intraperitoneally daily in mice for 6 days before challenge with LPS. In addition,10 mice in the normal saline group(NS group) were administered saline also by intraperitoneal injection at the same time in the same way. Ten animals in each group were killed at 4 h after LPS administration respectively. Wet /dry weight ratios of lung,the expression of NF--资Bp65 was observed by immunohistochemistry,the levels of IL-1βand IL-6 in lung tissue were measured by ELISA,and lungs histopathology was also performed. Results: Compared with NS group,wet /dry weight ratios of lung,the expression levels of NF--资Bp65,IL-1βand IL-6 in lung tissue were significantly higher in the LPS group(P < 0.01). Alveolar edema and neutrophils infiltration were observed in LPS group. Mildronate pretreatment significantly attenuated LPS-induced pulmonary histological changes in MIL 50 mg/kg group,MIL 100 mg/kg group and MIL 200 mg/kg group(P < 0.05),and there was no significance in pulmonary histological changes among the three mildronate therapeutic groups. Conclusion: Mildronate can protect the lungs against LPS-induced acute injury by down-regulating the expression of NF--资Bp65 and inhibiting inflammatory response at all doses.