Introduction: The optimal antiplatelet therapy following Left atrial appendage occlusion (LAAO) in atrial fibrillation patients who are not candidates for long-term oral anticoagulation therapy (OAC) is subject to debate. Hypothesis: Is single antiplatelet therapy (SAPT) safe and effective when compared to dual antiplatelet therapy (DAPT) in patients with high bleeding risk? Methods: We conducted a comprehensive search for all studies that compared the use of SAPT with DAPT following LAAO for patients in whom OAC is deemed highly risky or contraindicated. The outcomes of our study were device-related thrombosis (DRT), stroke and systemic embolization (SSE), and major bleeding (MB). The risk ratio (RR) with 95% confidence intervals (CIs) are presented as summary statistics and were calculated using a random-effects model. Results: A total of 15 observational studies with 3231 patients (SAPT, n=1036; DAPT, n=2195; 64.5% men; median follow-up duration 12 months; mean age 74.7±8.5 years; CHA2DS2-VASc score 4.3±1.6; HASBLED score 3.2±1.2) were included. For DRT, data were available from 10 studies (2910 patients); there was no difference between SAPT and DAPT groups (2.6% vs. 2.3%; RR: 1.41; 95%CI: 0.77-2.59; P=0.26; I 2 :0%). For SSE (8 studies, 959 patients); although numerically more events were observed in the SAPT group, there was no statistical difference between the two groups in the pooled analysis (2.9% vs. 1.5%; RR: 5.43; 95%CI: 0.74-39.81; P=0.1; I 2 :78%). Finally, for MB (8 studies, 1818 patients); although numerically more events were observed in the DAPT group, there was no statistical difference between the two arms (2.3% vs. 3.2%; RR: 1.90; 95%CI: 0.46-7.87; P=0.37; I 2 :72%). Conclusions: Our study showed comparable safety and efficacy profiles for SAPT and DAPT after LAAO. Adequately powered randomized studies determining the optimal antithrombotic therapy in the first weeks after LAAO are warranted in patients at high risk for bleeding.