Background: Four randomized controlled trials (RCTs) did not show benefit of direct oral anti-coagulant (DOAC) compared with antiplatelet therapy for prevention of recurrent stroke in pa-tients with embolic stroke of undetermined source (ESUS). However, the balance between efficacy and safety in subgroups need better definition. We aimed to assess the relative benefit of DOACs in key subgroups of adult patients with ESUS. Methods: We searched major databases (PubMed, Embase, CENTRAL, and Web of Science) for RCTs published from inception to 16 June 2024. The primary outcome was recurrent stroke, and the main safety outcomes were major bleeding and clinically relevant non-major bleeding (CRNB). We assessed risk of bias using the Cochrane Risk of Bias tool 2. Results: We identified four RCTs, involving a total of 13,970 patients with ESUS. Compared to antiplatelet therapy, treatment with DOAC did not reduce the risk of recurrent stroke (RR 0.95, 95%CI 0.83-1.08, p=0.45), ischemic stroke reduced (RR 0.92, 95%CI 0.80-1.05, p=0.22) or increase major bleeding (RR 1.57, 95%CI 0.87-2.83; p=0.14). DOAC was associated with a significantly higher risk of CRNMB compared to aspirin (RR 1.52, 95% CI: 1.22-1.90; p=0.0002). Subgroup analysis demonstrated that use of DOACs was associated with a significant protective effect in patients aged 75 or older (RR 0.76, 95% CI 0.60-0.97, p=0.03) and when the time from index stroke to randomization was ≥8 days (RR 0.80, 95% CI 0.66-0.97, p=0.02) in preventing re-currency of any type of stroke. Conclusion: Our meta-analysis showed lack of overall benefit of anticoagulation with DOAC compared to antiplatelet therapy for recurrent stroke prevention in adult patients with ESUS. However, subgroup analyses suggest the possibility of interactions between age and timing of randomization since stroke with treatment with DOAC in terms of recurrent stroke prevention. Further research toward tailoring the antithrombotic strategy ac-cording to patient characteristics are needed.