Patent foramen ovale (PFO) is more common in patients with stroke than in matched controls, but the stroke mechanism and late prognosis are not well known. We studied features, coexisting causes, and recurrences of stroke in 140 consecutive patients (mean age 44 +/- 14 years) with stroke and PFO admitted to a population-based primary-care center. We selected the patients from 340 patients (41%) aged < or = 60 years with acute stroke. The initial event was brain infarction in 118 patients (84%) and TIA in 22 (16%). Intracranial embolic occlusions were present on angiography or transcranial Doppler in most patients admitted within 12 hours of onset, whereas a venous source was clinically apparent in only six patients (5.5%). Pulmonary embolism, Valsalva maneuver at onset, and coagulation abnormalities were rare, but one-fourth of the patients had an interatrial septum aneurysm (ISA) that coexisted with PFO. An alternative cause of stroke was present in only 22 patients (16%), usually cardiac (atrial fibrillation, severe mitral valve prolapse, akinetic left ventricular segment). During a mean follow-up of 3 years, the stroke or death rate was 2.4% per year, but only eight patients had a recurrent infarct (1.9% per year). This low rate of recurrence contrasted with the severity of initial stroke, which left disabling sequelae in one-half the patients. Multivariate analysis showed that interatrial communication, a history of recent migraine, posterior cerebral artery territory infarct, and a coexisting cause of stroke were associated with recurrence, whereas ISA and treatment type (coagulant or antiaggregant therapy, surgical closure of PFO) were not. However, given the low number of events, these findings must be taken with caution. In conclusion, our study shows that stroke associated with PFO with or without ISA is not commonly due to a coexisting cause of stroke. It is usually embolic, although a definite source cannot often be demonstrated. The presenting stroke is often severe, but recurrence is uncommon. The demonstration of factors associated with a higher risk of recurrence in subgroups of patients is critical for the long-term management of these patients.