Objectives: To report long-term safety and efficacy of combined percutaneous LAA and PFO/ASD closure. Methods: A retrospective study of 370 consecutive patients undergoing LAAC procedures using the Watchman (WM) device. Data were compared between 330 cases only with LAAC procedure (Group I) and 25/5 (PFO/ASD) cases with sequential procedures of LAAC and PFO/ASD closure (Group II). Results: Compared to Group I, Group II had more males (86.7% vs. 65.8%, p < 0.05) and a higher rate of stroke (33.3% vs. 10.6%, p < 0.01), but there were no statistical differences in the remaining patient characteristics. During the follow-up period, there were no significant differences between the two groups in embolism events (6.1% vs. 0%, p = 0.39), device related thrombus (5.8% vs 3.3%, p = 1.0), major bleeding (9.4% vs. 6.7%, p = 1.0) and cardiac death (3.6% vs. 0%, p = 0.61). The observed rate of all thromboembolic events by Kaplan-Meier analysis was decreased by 39.9% and 100% and the observed annual rate of bleeding was reduced by 32.9% and 57.6% in Group I and Group II, respectively. Conclusions: LAAC combined with PFO/ASD closure might be an ideal choice to prevent stroke and other thrombotic complications in patients with both NVAF and PFO/ASD.