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<b>Background</b>. Patients with β-thalassemia have a high incidence of atrial fibrillation (AF) and other supraventricular arrhythmias. The use of non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prophylaxis in patients with β-thalassemia has not been systematically evaluated. <b>Methods.</b> We enrolled patients with transfusion-dependent β-thalassemia, who were on treatment with NOACs for thromboembolic prophylaxis of supraventricular arrhythmias. Data on thromboembolic and bleeding events were collected. <b>Results.</b> Eighteen patients were enrolled. The patients had a history of AF (sixteen), typical atrial flutter (five), and atypical atrial flutter (four). The patients were treated with dabigatran (seven), apixaban (five), rivaroxaban (four) or edoxaban (two). The mean follow-up duration was 22 ± 15 months. No thromboembolic events were reported. No major bleedings were observed. Three patients had non-major bleeding events. Two patients reported dyspepsia during treatment with dabigatran and were shifted to a different NOAC. <b>Conclusions.</b> Our study suggests the efficacy and safety of NOACs in patients affected by transfusion-dependent β-thalassemia.