Background: Percutaneous device closure was shown to effectively prevent recurrent strokes in patients with patent foramen ovale (PFO). Whether this protective effect is relevant for patients with hypercoagulable states (HCSs) is unknown as they were not represented in prior studies. Methods: Data on 136 consecutive patients with a PFO and clinically significant HCS were retrospectively collected. PFO closure and antithrombotic regimen were decided on an individual basis by the treating physicians, and adherence to therapy was routinely evaluated. The outcome was the occurrence of cerebrovascular accident (CVA) or transient ischemic attack (TIA). Results: HCS types consisted of antiphospholipid syndrome (31%), factor-5 Leiden mutation (22%), prothrombin mutation (18%), protein S deficiency (15%), protein C deficiency (7%), methyl-tetra-hydro folate reductase mutation (5%), and essential thrombocytosis (2%). 102 patients (75%) were maintained on anticoagulants and the remaining on antiplatelet therapy. PFO closure was undertaken in 85 (63%); antithrombotic therapy was not interrupted prior to or after the procedures. At a mean follow-up of 46 ± 8 months, 23 patients (17%; 95% confidence interval, 9.3–22%) experienced an outcome event, mainly in the form of CVAs (n = 15, 65%). In multivariable analysis, PFO closure was associated with a 5-fold decrease in the risk of CVA/TIA (p = 0.02). This effect was independent of the type of HCS or antithrombotic therapy. Conclusions: Among patients with HCSs maintained on anticoagulant or antiplatelet therapies, PFO closure was associated with a significantly lower risk of CVA or TIA.