Oral dabigatran etexilate is indicated for the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF) in whom anticoagulation is appropriate. Based on the RE-LY study we investigated the cost-effectiveness of Health Canada approved dabigatran etexilate dosing (150 mg bid for patients <80 years, 110 mg bid for patients ≥80 years) versus warfarin and “real-world” prescribing (i.e. warfarin, aspirin, or no treatment in a cohort of warfarin-eligible patients) from a Canadian payer perspective. A Markov model simulated AF patients at moderate to high risk of stroke while tracking clinical events [primary and recurrent ischaemic strokes, systemic embolism, transient ischaemic attack, haemorrhage (intracranial, extracranial, and minor), acute myocardial infarction and death] and resulting functional disability. Acute event costs and resulting long-term follow-up costs incurred by disabled stroke survivors were based on a Canadian prospective study, published literature, and national statistics. Clinical events, summarized as events per 100 patient-years, quality-adjusted life years (QALYs), total costs, and incremental cost effectiveness ratios (ICER) were calculated. Over a lifetime, dabigatran etexilate treated patients experienced fewer intracranial haemorrhages (0.49 dabigatran etexilate vs. 1.13 warfarin vs. 1.05 “real-world” prescribing) and fewer ischaemic strokes (4.40 dabigatran etexilate vs. 4.66 warfarin vs. 5.16 “real-world” prescribing) per 100 patient-years. The ICER of dabigatran etexilate was $10,440/QALY versus warfarin and $3,962/QALY versus “real-world” prescribing. This study demonstrates that dabigatran etexilate is a highly cost-effective alternative to current care for the prevention of stroke and systemic embolism among Canadian AF patients.