Background: This work was to investigate the effect of different doses of hydrocortisone (HC) on rats with septic encephalopathy. Material and methods: Wistar rats of clean grade, 5-6 weeks old, were randomly divided into Lipopolysaccharide (LPS) group, high-dose hydrocortisone group, medium-dose hydrocortisone group, low-dose hydrocortisone group, and sham group (n=10). Except sham group, rats of other group were injected LPS, 25 mg/kg, i.v. 6 hours later, neuron-specific enolase (NES) in serum and brain water content were tested, and pathological changes were observed by light microscope and electron microscope. Results: Compared with sham group, LPS group demonstrated significantly higher levels of serum NES, brain water content and pathological scores (P<0.05). Different doses of HC ameliorated the injury induced by SE to different extent. Conclusion: HC decreased serum NES, lessened brain water content and relieved pathological changes of brains, which indicate that HC is likely to protect brain injury caused by SE; besides, low dose of HC has the best efficacy and high dose of HC has the worst efficacy.