Objective To compare the efficacy and safety between calcium-containing and calcium-free replacement solution in continuous renal replacement therapy with regional citrate anticoagulation. Methods The study included a total of 78 patients who underwent continuous renal replacement therapy (CRRT) with regional citrate anticoagulation in the Intensive Care Unit of the Emergency Medical Department at the Affiliated Hospital of Xuzhou Medical University. Following the application of inclusion and exclusion criteria, a final enrollment was made, resulting in two groups: calcium-containing replacement solution group (41 cases) and calcium-free replacement solution group (37 cases), determined using a random number table method.Both groups of patients were treated with continuous venous hemodiafiltration (CVVHDF) postdilution therapy mode, anticoagulation scheme, calcium and potassium ion supplement mode were the same.Record two sets of general information, etiology, APACHE II score, SOFA score, and laboratory indicators; Compare the lifespan of blood filters and renal function recovery during CRRT between two groups of patients; Record the levels of serum ionized calcium and filtered ionized calcium during the treatment period, as well as the amount of replacement solution, citric acid, and calcium gluconate used; Compare ICU stay time, 28 day mortality rate of follow-up patients, and incidence of complications.Results A total of 170 treatments (83 in calcium-containing group and 87 in calcium-free group) were performed. The filter lifespan was 55.80±8.82 hours in the calcium-containing group and 53.46±5.70 hours in the calcium-free group, with no significant difference between the two groups (P0.05). The serum ionized calcium concentration of calcium-containing replacement fluid group was slightly lower than that of calcium-free group, while the post-filter ionized calcium concentration of calcium-containing replacement fluid group was slightly higher than that of calcium-free group (P0.05).The dosage of calcium gluconate used in calcium replacement solution group was significantly lower than that in calcium replacement solution group (P0.05).There was no significant difference in ICU stay time, 28-day mortality, renal function recovery rate, the incidence of complications and citrate dose between the two groups (P0.05). Conclusion The use of regional citrate anticoagulation in CRRT, with both calcium-containing and calcium-free replacement solutions, yields comparable outcomes in terms of filter lifespan, hospital mortality, and renal recovery.The utilization of calcium-containing replacement solution in CRRT for critically ill patients offers enhanced convenience compared to the preparation of self-made solutions and high-dose intravenous calcium supplementation.