Objectives: This multi‐centre study reports safety and efficacy of percutaneous patent foramen ovale (PFO) closure, using the fourth generation Intrasept™ device. Background: PFO has been associated with paradoxical embolism and cryptogenic stroke. Percutaneous PFO closure seems to reduce the risk for recurrent paradoxical thrombo‐embolism. Currently, different devices are used for PFO closure. Methods: Patients, who underwent a PFO closure with the Intrasept device (Cardia, Eagan, MN) between July 2002 and September 2006, were included in the study. The primary endpoint was defined as reoccurrence of stroke, transient ischemic attack (TIA), or peripheral thrombo‐embolism. Peri‐procedural and mid‐term complications were reported. Results: Four‐hundred thirty patients (mean age 50.7 ± 13.0 years, 231 men) underwent closure. The indications were cryptogenic stroke (69.8%), TIA (23.5%), peripheral embolism (3.3%), and other (3.5%). The median follow‐up time was 0.8 years, range 3.9 years. The primary endpoint occurred in 0.5% for stroke, in 2.5% for TIA, and in none for peripheral embolism. Peri‐procedural complications were reported in 11.5% of cases, from which 0.2% was defined as major. No severe complications occurred during mid‐term follow‐up. A residual shunt was present in 12.5% of patients who did not suffer from a recurrent event, compared to 36.4% of patients who reached the primary endpoint (P = 0.04). Conclusion: This multi‐centre study suggests that percutaneous closure of a symptomatic PFO with the fourth generation Intrasept device is safe and might be effective to prevent the recurrence of paradoxical thrombo‐embolic events. © 2008 Wiley‐Liss, Inc.