Background <p>Atrial fibrillation and chronic kidney disease mutually interact, presenting distinct clinical dilemmas where the optimal risk–benefit profile of antithrombotic therapy remains undefined.</p> Methods <p>This study was conducted using the Korean Health Insurance Review and Assessment Service database in patients with atrial fibrillation undergoing hemodialysis. The primary outcomes included thromboembolism and intracranial hemorrhage rates, while major bleeding and all-cause death were secondary outcomes. Selecting patients not taking antithrombotics as a reference, Kaplan–Meier and Cox proportional hazard analyses were performed for those taking antiplatelets, direct oral anticoagulants (DOACs), and warfarin. The net clinical benefit was obtained by balancing the efficacy and safety of each antithrombotic therapy.</p> Results <p>There were 13,311 patients on hemodialysis&#xa0;recorded as with atrial fibrillation, the mean age was 63.1 ± 12.8&#xa0;years, with the&#xa0;mean CHA₂DS₂-VASc score of 3.3 ± 1.6. One-fifth of the&#xa0;patients received antithrombotic therapy, with 67.1% using antiplatelet&#xa0;drugs. Warfarin was associated with an increased thromboembolic risk (HR 1.25; 95% CI, 1.01–1.56), while findings for&#xa0;DOACs remain inconclusive. In net clinical benefit analysis, with warfarin demonstrated the most unfavorable profile, and&#xa0;DOACs exhibited comparable net clinical benefit to antiplatelet&#xa0;agents (0.57; 95% CI, −&#xa0;0.56–1.70).</p> Conclusion <p>This study provides real-world evidence on the use of antithrombotic therapy in atrial fibrillation patients undergoing hemodialysis. The findings highlight the profound complexity and uncertainty in managing this high-risk population, underscoring the importance for comprehensive assessment, individualized treatment approaches, and further dedicated research to establish optimal prevention&#xa0;and treatment strategies.</p> Graphical abstract <p></p>