Background There are inadequate data on the optimal strategy for transitioning factor Xa inhibitors (FXai; apixaban, rivaroxaban) to unfractionated heparin (UFH) infusions. Objective In patients transitioning from an FXai to an UFH infusion, this study compared the safety and efficacy of monitoring UFH infusions using an activated partial thromboplastin time (aPTT) titration scale versus utilizing an UFH-calibrated anti-Xa titration scale aided by a novel institutional guideline. Methods A retrospective cohort analysis was conducted on adult patients transitioning from an FXai to an UFH infusion at 2 medical centers from June 1, 2018, to November 1, 2020. One institution utilized aPTT while the other institution primarily used UFH-calibrated anti-Xa. The primary endpoint was a composite of death, major bleeding, or new thrombosis during the hospitalization with a planned noninferiority analysis. Secondary outcomes were also collected including the amount and duration of UFH administered between cohorts. Results The incidence rate of the primary composite endpoint was 6.3% in the anti-Xa group and 11% in the aPTT group ( P < 0.001 for noninferiority, P = 0.138 for superiority) meeting noninferiority criteria. No statistical differences were seen in new thrombosis, major bleeding, or any bleeding. Conclusion and Relevance This represents the first report of a comparison between aPTT versus anti-Xa monitoring in relation to clinical outcomes for patients transitioning from an FXai to an UFH infusion. A transition guideline primarily utilizing an UFH-calibrated anti-Xa assay appears to be a safe alternative to aPTT monitoring and can aid facilities in the management of patients during these complex transitions.