OBJECTIVES:  To determine the cost-effectiveness of the left atrial appendage closure (LAAC) device compared with warfarin or novel oral anticoagulants (apixaban, dabigatran, rivaroxaban) in patients with nonvalvular atrial fibrillation (NVAF) from an Ontario, Canada, public payer perspective. METHODS:  A microsimulation model was adapted to assess the cost-effectiveness of the LAAC device compared with apixaban, dabigatran, rivaroxaban, and warfarin over a lifetime horizon. Patients’ baseline characteristics were obtained from an Ontario new onset atrial fibrillation cohort (n=35,143). The analysis incorporated CHADSVASc and HAS-BLED risk scores to determine baseline risks of thromboembolic and hemorrhagic events. Treatment effects and adverse events for the LAAC device were obtained from the PROTECT AF and PREVAIL trials. Clinical event costs were primarily obtained from Ontario costing studies and adjusted to 2016 Canadian dollars. Monte Carlo simulation was preformed using 1,000 inner loops and 10,000 outer loops to determine the average base case incremental cost, incremental QALYs, and incremental cost-effectiveness ratio of the LAAC device relative to the oral anticoagulant alternatives. Deterministic, probabilistic, and scenario-based sensitivity analyses were performed to examine uncertainty in the results. RESULTS:  Over a lifetime horizon, the LAAC device was not cost-effective (ICER: $272,216/QALY) relative to warfarin and was dominated (higher costs, lower QALYs) by each apixaban, dabigatran, and rivaroxaban. In the majority of sensitivity analyses the device remained not cost-effective. The device was shown to be cost-effective relative to warfarin and rivaroxaban when a decreased risk of ischemic stroke for LAAC patients was examined. CONCLUSIONS:  The LAAC device was not cost-effective relative to warfarin or novel oral anticoagulants in patients with NVAF. These value for money results ought to be considered when making funding recommendations concerning the adoption of this technology in the health care system.