We investigated the efficacy of transcatheter patent foramen ovale (PFO) closure to prevent recurrent cerebral ischemic events in patients who did and those who did not have thrombophilia. Patients who have a PFO and an associated thrombophilia may have an increased risk of cerebral ischemic events. Seventy-two consecutive patients (mean age 42 +/- 13 years) underwent percutaneous PFO closure because of a cerebral stroke (51%) or a transient ischemic attack (49%). A thrombophilia was found in 20 patients (28%). A large right-to-left shunt through the PFO was found in 44 patients (61%) and an atrial septal aneurysm was found in 39 (54%). After the first event, 18 of 20 patients (90%) with a thrombophilia received oral anticoagulation. Before closure, patients who had a thrombophilia also had a higher rate of recurrences than patients who did not (p <0.0001), despite a similar follow-up (p = 0.14) and regardless of shunt entity (p = 0.59), presence of an atrial septal aneurysm (p = 0.98), and a prevalence of cardiovascular risk factors (p = 0.44). PFO closure was successful in all patients. Five patients (8%) had a residual shunt at 6 months. At 20 +/- 11 months after PFO closure, 3 recurrent events occurred (4%), and the recurrence rate was similar in patients who did and those who did not have a thrombophilia (p = 0.25). Thus, in patients who have a cryptogenic stroke, the association of a PFO with a thrombophilia significantly increases the risk of recurrences. Thus, transcatheter PFO closure is effective for preventing recurrences in patients who have a thrombophilia.