Regional citrate anticoagulation (RCA) is internationally recommended as the standard anticoagulation strategy for high-bleeding-risk patients undergoing continuous renal replacement therapy (CRRT). This study aimed to compare the efficacy and safety of nafamostat mesylate (NM) with RCA in patients at risk of severe hemorrhagic complications. We conducted a prospective, randomized controlled trial involving 80 high-bleeding-risk patients who received CRRT in the Department of Nephrology at the Second Affiliated Hospital of Nanchang University between April 2023 and August 2024. Participants were randomly assigned to receive either NM or RCA for anticoagulation. The primary endpoint was the initial filter lifespan and the incidence of filter coagulation, while other endpoints focused on safety outcomes. The study cohort comprised 80 patients (40 in the NM group and RCA group, respectively). Since all patients underwent daytime CRRT, the median initial filter lifespan both in the NM and the RCA group was 10 hours. There was no significant difference between the two groups (P=0.720); At the termination of CRRT, in the NM group 16 filters (40%) developed grade I coagulation, while 28 filter (70%) developed grade I coagulation in the RCA group (P=0.007). There were 10 cases (25%) of all adverse events in the NM group and 16 cases (40%) in the RCA group, with no difference between the two groups (P=0.152). Therefore, we consider that in high-bleeding-risk patients undergoing CRRT, NM appears to confer more effective anticoagulation than RCA without increasing hemorrhagic risk.