Nafamostat mesilate (NM), a synthetic serine protease inhibitor, has been used increasingly as an anticoagulant during continuous renal replacement therapy (CRRT). However, there, are limited data from randomized studies on NM use in patients with a bleeding tendency. This prospective study evaluated the efficacy and safety of NM use during CRRT in patients with acute kidney injury (AKI) patients at high risk of bleeding.Patients with AKI at high risk of bleeding were randomized into the NM and no anticoagulant (NA) groups. The primary outcome was the treatment efficacy represented by the filter lifespan. Several parameters, including safety and patient survival rates at 30 and 90 days, were analyzed as secondary outcomes.Fifty-five patients were included in this study (NM group = 31, NA group = 24). The baseline characteristics did not significantly differ between the groups. The mean filter lifespan was significantly longer in the NM group than in the NA group (31.7 ± 24.1 versus 19.5 ± 14.9 hours; P = 0.035). The most common cause of filter failure was filter clotting, which was significantly more frequent in the NA group than in the NM group (59.6% versus 37.7%, P = 0.024). The Cox proportional hazards model showed a 42.2% longer filter lifespan in the NM group compared with the NA group (hazard ratio, 0.578; 95% confidence interval, 0.362–0.923; P = 0.022). There were no significant differences in the frequencies of transfusions and major bleeding between the groups. Patient survival rates at 30 and 90 days after CRRT initiation were comparable between the groups.Nafamostat mesilate is a safe and effective anticoagulant for CRRT and allows sufficient filter survival without increasing the risk of bleeding in critically ill patients with AKI and bleeding tendencies.