Objectives We sought to examine acute and midterm results of closure of multiple interatrial communications with staged device deployment and to review the relevant literature. Background Information about percutaneous methods of closure for multiple defects is limited. Methods We treated 148 patients with multiple defects. Of these, 88 had a relevant left to right shunt (“LRS”), 52 had a presumed paradoxical embolism (“PPE”), five had both (LRS and PPE), and one patient, respectively, had migraine, decompression sickness, and a right to left shunt. After implantation of the first device, closure of additional septal defects was attempted only if indicated clinically. Results Ninety-four patients received a single device and 53 more than one. In four patients, surgical defect closure followed. At the end of follow-up (FU; mean 4.5 ± 3.4 years), complete closure of all defects occurred in 67.6% (62.1% for LRS, 76.5% for PPE). Clinical success (small or trivial residual shunt) was achieved in 86.9% (83.9% for LRS, 90.2% for PPE). Complications included pericardial effusions in 2.7%, recurrent thromboembolic events in 4.8%, and new onset of atrial fibrillation in 10.1%. In a significant number of patients with multiple defects, after single device implantation, the likelihood of complete closure increased with FU time (26% complete closure at 1 month vs. 78% at 24 months). Conclusion Percutaneous closure of multiple interatrial communications is feasible and safe. Importantly, many residual defects close without further intervention at FU. Therefore, staged device delivery is an alternative to simultaneous device implantation, possibly requiring fewer and smaller second devices. © 2012 Wiley Periodicals, Inc.