Objective: To preliminarily observe the efficacy and safety of switching to nafamostat (NM) combined with regional citrate anticoagulation (RCA) in patients receiving continuous renal replacement therapy (CRRT) who exhibited inadequate anticoagulation with RCA alone or RCA combined with low molecular weight heparin (LMWH). Methods: Patients admitted to the intensive care unit receiving CRRT with initial anticoagulation using 4% RCA alone or combined with LMWH were enrolled. The filter lifespan was less than 24 hours for two consecutive sessions, the anticoagulation regimen was switched to NM combined with RCA. The filter lifespan after switching, changes in coagulation parameters and blood cell counts, as well as bleeding complications were observed. Results: A total of 53 patients were enrolled, 34 of whom were at high risk of bleeding. Among them, 34 received initial anticoagulation with RCA alone and 19 with RCA combined with LMWH. The median average filter lifespan with initial anticoagulation was 13.0 (9.6, 17.0) hours. After switching to NM combined with RCA, the median average filter lifespan significantly increased to 31.5 (22.9, 44.7) hours (P<0.001). Among 124 sessions with NM combined with RCA anticoagulation, 76 sessions (61.3%) achieved a filter lifespan exceeding 24 hours, including 10 sessions that reached 72 hours. NM combined with RCA did not significantly affect coagulation parameters, white blood cell count, hemoglobin level, or platelet count. No bleeding complications were observed. Conclusion: When anticoagulation with RCA alone or combined with LMWH is ineffective during CRRT, switching to NM combined with RCA can prolong filter lifespan without significantly affecting coagulation function or increasing bleeding risk. This regimen may serve as a potential alternative anticoagulation strategy for CRRT.