Left atrial appendage occlusion (LAAO) is an approved alternative for stroke prevention in atrial fibrillation for patients with an "appropriate rationale" to avoid long-term oral anticoagulation (OAC). Many patients undergoing LAAO are at high risk of bleeding.This study sought to investigate whether dual antiplatelet therapy (DAPT) is a safe alternative to OAC (direct oral anticoagulation [DOAC] or warfarin) with aspirin after LAAO.Using National Cardiovascular Data Registry LAAO registry data, patients undergoing Watchman FLX (Boston Scientific) implantation (August 5, 2020-September 30, 2021) were included in 1:1 propensity-matched analyses comparing discharge medication regimens (DAPT, DOAC/aspirin, or warfarin/aspirin). A composite endpoint (death, stroke, major bleeding, and systemic embolism), its components, and device-related thrombus between discharge and 45 days were evaluated.In 49,968 patients implanted with the Watchman FLX during the study period, the mean age was 77 years, and 40% were women. Postimplant DOAC/aspirin was prescribed in 24,497 patients, warfarin/aspirin in 3,913, and DAPT in 4,155. DAPT patients had more comorbid conditions than patients receiving OAC/aspirin. After propensity score matching, the 45-day composite endpoint rates were similar among the groups (DAPT = 3.44% vs DOAC/aspirin: 4.06%; P = 0.13 and DAPT = 3.23% vs warfarin/aspirin: 3.08%; P = 0.75). Death, stroke, and device-related thrombus were also similar; major bleeding was slightly increased in DOAC/aspirin patients (DAPT = 2.48% vs DOAC/aspirin = 3.25%; P = 0.04 and DAPT = 2.25% vs warfarin/aspirin = 2.22%; P = 0.93).In a large registry, DAPT had a similar safety profile compared with current Food and Drug Administration-approved postimplant drug regimens of OAC with aspirin following LAAO with the Watchman FLX. Shared decision making for nonpharmacologic stroke prevention should include a discussion of postprocedure medical therapy options.