Background: Optimal antithrombotic therapy after left atrial appendage (LAA) occlusion is still not clear. The aim of this study was to investigate the role of different antithrombotic regimens after the procedure. Methods and Results: We retrospectively analyzed data of 260 patients who underwent LAA occlusion and divided them into four groups according to therapy at discharge: dual antiplatelet therapy (group A, 71.5%); oral anticoagulants (group B, 19%); “minimal” antithrombotic therapy (single antiplatelet agent or without any antithrombotic therapy; group C, 4.5%) and other therapeutic regimens (such as a combination of antiplatelets and anticoagulants; group D, 4.5%). We analyzed baseline characteristics, procedural data, and clinical and transesophageal follow-up for each group. The incidence of adverse events was low in the whole population and had a similar distribution among groups. The majority of bleeding events was registered during the first 3 months after the procedure (34 out of 46, 70%). Ischemic events (2%), as well as silent left atrial thrombosis, were rare and not significantly higher in the population discharged with “minimal” antithrombotic therapy. Conclusion: Our experience seems to suggest that LAA occlusion was associated with a low incidence of adverse events, regardless of antithrombotic therapy. A “minimal” drug regimen may be feasible without losing efficacy on embolic prevention for patients with high bleeding risk.