Continuous renal replacement therapy (CRRT) has emerged as the preferred dialysis modality for critically ill patients with acute kidney injury. The objectives of this retrospective study were to assess the effect of nafamostat on circuit patency of CRRT and the safety regarding bleeding complications in patients at high risk of bleeding. We conducted a retrospective study of 243 CRRT patients at high risk of bleeding. We started CRRT without anticoagulation, and nafamostat was used if hemofilter lifespan was less than 12 h. The average hemofilter lifespan was measured before and after drug infusion to evaluate the efficacy of nafamostat. The frequency and number of red blood cell (RBC) transfusions were measured to assess the safety of nafamostat. Of the 243 patients, 62 (25.5%) received nafamostat. In nafamostat group, the hemofilter lifespan was lengthened from 10.2 (7.5-13.0) h to 19.8 (12.6-26.6) h after drug infusion (p < 0.001). The hemofilter lifespan was 27.5 (17.5-38.2) h in anticoagulation-free group. The frequency of RBC transfusion during CRRT did not differ between the nafamostat group and the anticoagulation-free group (71% vs. 70%, p = NS). The median number of RBC units transfused per CRRT day was also not different between the two groups [0.7 (0.5-1.0) units/day vs. 0.7 (0.4-1.1) units/day; p = NS]. The use of nafamostat in patients at high risk of bleeding who require CRRT effectively lengthened the filter survival time without an increase in RBC transfusion. However, 74.5% of patients at high risk of bleeding maintained an acceptable CRRT hemofilter lifespan without circuit anticoagulation.