Abstract Background Patients with atrial fibrillation (AF) and end-stage renal disease on chronic haemodialysis (HD) are at risk for thromboembolic and bleeding events. The safety and efficacy of direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in this population remains unclear. Purpose This systematic review and meta-analysis aimed to compare DOACs with VKAs in patients with AF on chronic HD with regards to cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, and major or life-threatening bleeding. Methods We systematically searched PubMed, EMBASE, and Cochrane Library for randomised controlled trials (RCTs) comparing DOACs with VKAs in patients with AF on chronic HD from inception to February 2023 in accordance with PRISMA guidelines. Statistical analyses were performed using Review Manager 5.4.1. Heterogeneity was evaluated using I2 statistics. We performed the data extraction following the intention-to-treat principle. Results We selected three RCTs including 341 patients, of whom 176 (51.6%) were randomised to DOACs. Follow-up ranged from 174 days to 3.38 years. There was no significant difference between groups in terms of cardiovascular mortality (RR 1.35; 95% CI 0.71–2.60; p=0.36; I2=0%; Fig. 1A), all-cause mortality (RR 0.99; 95% CI 0.76–1.30; p=0.96; I2=11%; Fig. 1B), ischaemic or uncertain type of stroke (RR 0.52; 95% CI 0.18–1.48; p=0.22; I2=0%; Fig. 2A), or major or life-threatening bleeding (RR 0.69; 95% CI 0.42–1.14; p=0.15; I2=20%; Fig. 2B), with an overall low between-study heterogeneity. Conclusion In this meta-analysis, no significant difference was observed between DOACs and VKAs in cardiovascular mortality, all-cause mortality, ischaemic or uncertain type of stroke, nor major or life-threatening bleeding in patients with AF on chronic HD.Figure 1Figure 2