Objective To explore the safety and efficacy of regional citrate anticoagulation in hemoperfusion combined with continuous renal replacement therapy (CRRT). Methods Patients who underwent continuous veno-venous hemodiafiltration tandem hemoperfusion between January 2021 and March 2022 in West China Hospital of Sichuan University were retrospectively enrolled. All patients received double-lumen catheter indwelling through internal jugular vein or femoral vein for vascular access, and were treated with Prismaflex V8.0 CRRT machine, extracorporeal circulation line ST150, and disposable hemoperperfusion device HA380. Four percent sodium citrate was pumped from the arterial end at the rate of 180-200 mL/h. The blood pump rate was 130-150 mL/min, the ratio of dialysis fluid to the dose of replacement fluid was 1∶1, the amount of CRRT treatment agent was 20-35 mL/(kg·h), replacement fluid was added by post-dilution method, and the treatment time of hemoperfusion was 8-10 h. The dialysis treatment completion rate, the cardiopulmonary bypass life, the incidence of coagulation events, and the levels of procalcitonin, C-reactive protein, interleukin-6, etc. were observed. Results A total of 143 cases of treatment were completed in 75 patients, among them, 119 cases were successfully completed and the completion rate of hemoperfusion treatment was 83.2%. The average life of hemoperfusion devices was (8.5±1.5) h. Bleeding or blood clotting occurred in 18.9% of the treatment (27/143), 13 cases had CRRT extracorporeal circulation coagulation, 11 cases had hemoperfusion device coagulation, and 3 cases had gastrointestinal bleeding. The ionic calcium levels after the filter of 93 cases of treatment were maintained around 0.25-0.35 mmol/L, and the peripheral calcium levels were maintained around 1.0-1.1 mmol/L. Compared with that at 0 h, the procalcitonin decreased significantly 72 h after hemoperfusion treatment (P=0.014), while there was no significant change in interleukin-6 or C-reactive protein after 72 h treatment (P>0.05). None of the patients experienced anaphylaxis during treatment. Conclusion In CRRT combined with hemoperfusion, the use of regional citrate anticoagulation results in good cardiopulmonary bypass life, inflammatory mediators clearance, and a lower risk of bleeding.