The objective of this study was to compare the effectiveness and safety of anti-Xa-guided management versus aPTT-guided management of intravenous (IV) unfractionated heparin (UFH) in patients with a durable ventricular assist device (VAD). This was a retrospective study conducted at a single academic medical center. Patients were included if they had a durable VAD and were managed using aPTT-guided UFH management from May 2019 to May 2020 or were managed using anti-Xa-guided UFH management from May 2021 to December 2021. The primary outcome of the study was the median time to goal anticoagulation post-initiation of UFH. Secondary outcomes included the percentage of time within the therapeutic range and the incidence of thromboembolic and bleeding complications. The study included 23 patients, 12 of whom were managed using anti-Xa-guided UFH, and 11 were managed using aPTT-guided UFH. The treatment arm using anti-Xa-guided UFH demonstrated a faster time to therapeutic anticoagulation goal range with a median time of 21.3 h [IQR = 12.2-34.8] compared to 37.3 h [IQR = 41-74] in the aPTT-guided UFH treatment arm (P = 0.03). In addition, the anti-Xa-guided UFH arm had a higher percentage of time within the therapeutic range, 76 % [IQR = 64.25-96.25] compared to 53 % [IQR = 41-74] in the aPTT-guided UFH arm (P = 0.04). Both arms had no significant differences in major bleeding events (P = 0.59) or clinically relevant minor bleeding events (P = 0.60) among patients. There was no incidence of thromboembolic events in either treatment arm. Based on this single-center experience, anti-Xa-guided UFH management resulted in a faster time to therapeutic anticoagulation and a longer time within the desired therapeutic range. The results suggest that anti-Xa-guided monitoring may be superior to UFH-guided monitoring in patients with a durable VAD.