Introduction: Double-filtration plasmapheresis (DFPP) is a semi-selective blood purification method based on dual filtration system. Regional citrate anticoagulation (RCA) is an appealing anticoagulation alternative in DFPP. However, there are still few reports on the safety of RCA in DFPP treatment. Objective: To investigate the anticoagulation effect and safety of RCA for DFPP in critical patients. Methods: A total of 34 critical patients treated with DFPP were retrospectively studied. The incidence of coagulation during extracorporeal circulation after single treatment was compared before and after treatment. Heart rate, systolic blood pressure, diastolic blood pressure, mean arterial pressure, blood routine indexes, blood gas analysis, peripheral ionic calcium (iCa), total peripheral calcium (TCa), TCa/iCa, and complications before and after single treatment were compared. The changes of transmembrane pressure, pressure drop were measured, and the indexes of coagulation before and after treatment were compared. Results: The blood coagulation 0.05). Level of TCa was significantly decreased at 5 min after treatment (p < 0.05), but there was no statistically significant difference at 6 and 24 h (p > 0.05). No treatment-related serious complications were observed in any of the patients. Conclusions: For critical patients who underwent DFPP procedure, RCA is safety and had significant anticoagulation effects, which is worthy of clinical application.