OBJECTIVE: To investigate the organ protective role and the underlying mechanism of nafamostat mesylate (NM) in a renal ischemia-reperfusion injury (RIRI) model. METHODS: A total of 21 healthy male Sprague-Dawley (SD) rats were randomly assigned to 3 groups ( RESULTS: 1) Compared with those of the Sham group, the levels of cystatin C, creatinine, and inflammatory factors in the RIRI and NM groups were significantly increased, and the expression levels in the NM group were lower than those in the RIRI group ( CONCLUSION: NM may play a protective role in a rat model of RIRI, and its underlying mechanisms may be related to the regulation of the functional abnormalities of HMGB1-mediated macrophages.