Background: The percutaneous closure of single atrial septal defect (ASD) is a valid alternative to surgery. Objectives: To assess the feasibility of percutaneous treatment of multiple ASDs. Methods: Between 1998 and 2007, 165 out of 1280 consecutive patients undergoing ASD percutaneous closure at our institution showed multiple defects that were classified in four categories: double atrial septal defects (d-ASD), multifenestrated atrial septal defects (f-ASD), multifenestrated defects with no signs of right heart overload (f-PFO), and complex cases (c-ASD). The following end points were taken into consideration: (1) immediate procedural success; (2) long term safety and efficacy. In this study, up to 81% of multiple ASDs were suitable for percutaneous closure. Results: Multiple device implantations were required in 47% of cases, especially in patients with d-ASD and c-ASD. Complication rate, residual shunt, and long term outcome were comparable among the four different categories. In particular, at long term follow-up (6 ± 2 years) no patient required further surgical or percutaneous treatment and complete closure was confirmed in 99% of cases. Conclusions: Percutaneous closure of multiple ASDs is feasible and associated with a good outcome. A thorough identification and analysis of morphological aspects are mandatory in order to select the appropriate device and the optimal strategy. © 2010 Wiley-Liss, Inc.