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Background: Regional citrate anticoagulation (RCA) is the preferred continuous kidney replacement therapy (CKRT) anticoagulation strategy for children in the USA. Nafamostat mesilate (NM), a synthetic serine protease, is used widely for CKRT anticoagulation in Japan and Korea. We compared the safety and efficacy of NM to RCA for pediatric CKRT. Methods: Starting June 2019, the most recent 100 medical records of children receiving CKRT with either RCA or NM were reviewed retrospectively, at one children's hospital in Japan (NM) and one in the USA (RCA). The number of hours a single CKRT filter was in use, was the primary outcome. Safety was assessed by bleeding complications for the NM group and citrate toxicity leading to RCA discontinuation or electrolyte imbalance in the RCA group. Results: Eighty patients received NM and 78 patients received RCA. Median filter life was longer for the NM group (NM: 38 [22, 74] vs. RCA: 36 [17, 66] h, p = 0.02). When filter life was censored for discontinuation other than clotting, the 60-h survival rate was higher for RCA (71% vs. 54%). The hazard ratio comparing NM over RCA varied over time (HR 0.7; 0.2–1.5, p = 0.33 at 0 h to HR 5.5; 1.3–23.7, p = 0.334 at 72 h). The lack of difference in filter survival persisted controlling for filter surface area, catheter diameter, and pre-CKRT platelet count. Major bleeding rates did not differ between groups (NM: 5% vs. RCA: 9%). Conclusions: RCA and NM provide satisfactory anticoagulation for CKRT in children with no difference in major bleeding rates. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]