BACKGROUND AND AIMS: Life-long direct oral anticoagulant (DOAC) therapy is recommended after catheter ablation for atrial fibrillation (AF) in high-risk patients (CHA2DS2-VA≥2). Long-term DOAC compliance is crucial for effective stroke prevention. This study seeks to evaluate long-term compliance measured by adherence and persistence to DOAC therapy following first-time catheter abltation for AF. METHODS AND RESULTS: All Danish patients undergoing first-time catheter ablation between 2017 and 2024 were identified through Danish registries. Patients were stratified by CHA2DS2-VA score 0, 1, and ≥2. Primary outcomes were adherence and persistence to DOAC therapy at 1, 2, and 3 years after first-time catheter ablation. Adherence was defined as the proportion of days covered (PDC) ≥80%. Persistence was assessed as the proportion of patients covered based on the most recent pharmacy redemption before specific time points, given a 20% grace period. A total of 13 438 patients (32.1% female) were included. At 3 years post-ablation, the proportion of adherent patients with CHA2DS2-VA ≥2 (n = 7322) was 87.6% [95% cinfidence interval (CI): 86.8-88.4]. Applying a sensitivity analysis with a PDC ≥90% threshold, the proportion was 78.8% (95% CI: 77.8-79.8%). Persistence was 73.0% (95% CI: 71.6-74.4%) at 3 years. Rates of thromboembolic outcomes were low with a total incidence rate of the combined outcome of ischaemic stroke, transient ischaemic attack and systemic embolism at 6.6 per 1000 person-years (95% CI: 5.8-7.4). The incidence of major bleeding was found at 7.1 per 1000 person-years (95% CI: 6.3-8.0) for the combined cohort. CONCLUSION: While adherence to DOAC therapy was acceptable in patients with CHA2DS2-VA≥2, persistence declined over time and more than 20% were non-persistent by 3 years. Efforts to improve effective long-term stroke prevention may be warranted. UNSTRUCTURED ABSTRACT: Life-long direct oral anticoagulant (DOAC) therapy is recommended after catheter ablation for atrial fibrillation in high-risk patients (CHA2DS2-VA≥2). Adherence and persistence to DOAC is crucial for effective stroke prevention.Danish patients undergoing first-time catheter ablation between 2017 and 2024 were identified through registries.A total of 13 438 patients were included. At 3 years post-ablation, the proportion of adherent and persistent patients with CHA2DS2-VA ≥2 (n = 7322) was 87.6% and 73.0%, respectively.Adherence to DOAC was acceptable in patients with CHA2DS2-VA≥2. More than 20% of patients were non-persistent by 3 years. Efforts to improve effective long-term stroke prevention may be warranted.