Background and Purpose: Dual antiplatelet therapy (DAPT) has not been assessed in the embolic stroke of undetermined source (ESUS). We systematically investigated the net comparative effectiveness of DAPT in patients with ESUS.Methods: Patients were divided into mono-antiplatelet therapy (MAPT) or DAPT groups. The primary outcome measure was the net adverse clinical and cerebral events (NACCE) over one year. The key secondary outcomes included the NACCE constituents. We used propensity scores and stabilized inverse probability of treatment weighting (IPTW) to balance possible confounders.Results: A total of 1,527 patients with ESUS were enrolled. The annual rates of NACCE were lower in the DAPT groups than in the MAPT groups (7.20% vs. 11.97%, respectively). After propensity score matching of IPTW, weighted Kaplan-Meier curves showed that the risk of NACCE was significantly lower in patients taking DAPT (HR: 0.51; 95% CI: 0.32–0.79; P = 0.003) and subgroup patients taking aspirin and clopidogrel (HR: 0.53; 95% CI: 0.30–0.92; P = 0.024) compared with those taking MAPT. The DAPT group had lower risks of any stroke (HR: 0.50; 95% CI: 0.23–1.06, P = 0.071) and major adverse cerebrovascular and cardiovascular events (HR: 0.53; 95% CI: 0.30–0.95, P = 0.032) compared to the MAPT group. The groups had no significant difference in the risk of major bleeding.Conclusions: DAPT is associated with a decreased risk of NACCE compared to MAPT in patients with ESUS. Randomized controlled trials are warranted to confirm the results and improve patient care.