Abstract: Objective To observe the effect of Schistosoma japonicum cysteine protease inhibitor (rSjCystatin) for treatment of lipopolysaccharide (LPS)-induced sepsis in mice. Methods After a week of adaptive feeding, 54 BALB/c mice were randomly divided into normal control group (group A), sepsis group (group B), and rSjCystatin intervention group (group C). The mice in group A received an intraperitoneal injection of PBS (100 μL), and those in groups B and C were injected with PBS (100 μL) containing LPS (10 mg/kg); the mice in group C were also intraperitoneally injected with 25 μg sjCystatin in 100 μL PBS 30 min after LPS injection. From each group, 10 mice were randomly selected 24 h after PBS or LPS injection for detecting serum levels of TNF-α, IL-6, and IL-10 using ELISA and the levels of ALT, AST, BUN, and Cr using automatic biochemical analyzer; the pathological changes in the liver, lung and kidney were observed with HE staining. The remaining 8 mice in each group were used for observing the changes in the general condition and the 72-h survival. Results The 72-h survival rates of the mice was 100% in group A, 0 in group B, and 36% in group C, showing a significant difference among the 3 groups (P<0.05). Compared with those in group A, the mice in group B exhibited obvious liver, lung, and renal pathologies with increased levels of ALT, AST, BUN, Cr, IL- 6, and TNF-α (P<0.05). Treatment with sjCystatin significantly lessened LPS- induced organ pathologies, lowered the levels of liver and renal functional indexes and the pro-inflammatory cytokines, and increased the serum level of IL-10 in the mice (P<0.05). Conclusion SjCystatin can produce a significant therapeutic effect on sepsis induced by LPS in mice.