Objective To investigate the safety and efficacy of two different anticoagulation regimens of fondaparinux and low molecular weight heparin (LMWH) in continuous renal replacement therapy (CRRT). Methods The clinical data of patients undergoing CRRT in West China Hospital of Sichuan University between October 2021 and April 2022 were retrospectively analyzed. The patients were divided into fondaparinux sodium group and LMWH group according to anticoagulation with fondaparinux or LMWH during CRRT. The general condition, life expectancy of cardiopulmonary bypass, coagulation events, bleeding events, hemoglobin, and coagulation function-related indicators were compared between the two groups. Results A total of 78 patients were finally included, including 38 in the LMWH group and 40 in the fondaparinux group. The age of the patients in the LMWH group was older than that in the fondaparinux group [76.0 (57.0, 85.0) vs. 63.0 (52.3, 76.0) years, P=0.016]. There was no significant difference in other clinical baseline conditions (including gender, vascular access site, and treatment indications) between the two groups (P≥0.05). The cardiopulmonary bypass life of patients in the fondaparinux group was better than that in the LMWH group [67.1 (35.0, 72.0) vs. 42.0 (20.0, 55.3) h, P=0.003]. The survival rate of cardiopulmonary bypass in the fondaparinux group at 24, 48, and 72 h were higher than that in the LMWH group (87.5% vs. 65.8%, P=0.023; 67.5% vs. 36.8%, P=0.007; 42.5% vs. 13.2%, P=0.004). The incidence of blood filter coagulation events in the fondaparinux group was lower than that in the LMWH group (50.0% vs. 84.2%, P=0.001). There was no significant difference in the incidence of coagulation events and mild bleeding events between the two groups (P>0.05). There was no significant difference in hemoglobin and coagulation function-related indicators between the two groups before and after CRRT (P>0.05). Conclusion The continuity of maintenance therapy with fondaparinux is better than that of LMWH, and the safety of both in the course of CRRT treatment is comparable.