<b><i>Purpose:</i></b> This study was aimed at evaluating the efficacy and safety of regional citrate anticoagulation (RCA) versus no-anticoagulation continuous venovenous hemofiltration (CVVH) in acute severe hypernatremia patients with increased bleeding risk. <b><i>Materials and Methods:</i></b> Acute severe hypernatremia patients with high bleeding risk who underwent CVVH in our center between January 2011 and October 2017 were considered as candidates. Patients who were &#x3c;18 years old, with hypovolemic hypernatremia, and had systemic anticoagulation were excluded. The included patients were divided into RCA and no-anticoagulation groups according to their anticoagulation strategy during CVVH and matched by age, sequential organ failure assessment scores, and vasopressor dependency. <b><i>Results:</i></b> Of the 64 included patients, no-anticoagulation and RCA were employed for CVVH in 23 and 41 patients, respectively. The serum sodium reduction rate (RRSeNa) was not significantly different between the no-anticoagulation and RCA groups (<i>p</i> = 0.729). Compared to no-anticoagulation, RCA significantly prolonged the circuit survival time (15 h [4.1–23.9] vs. 51 h [21.3–80.7], <i>p</i> = 0.001). The incidence of filter failure was 65.2% (15/23) in the no-anticoagulation group and 2.4% (1/41) in the RCA group (<i>p</i> &#x3c; 0.001), respectively. In the matched cohort, the RRSeNas were not different between the 2 groups (<i>p</i> = 0.569), and the filter lifespan was significantly longer in the RCA group as well (<i>p</i> &#x3c; 0.001). <b><i>Conclusion:</i></b> RCA might be safe and effective for acute severe hypernatremia patients who underwent CVVH treatment. Further prospective, randomized, control trials are warranted to obtain robust evidences.