Patent foram ovale (PFO) is the most common anatomical cause of an interarterial shunt. It is usually asymptomatic but may cause paradoxical embolism and is a risk factor for non-lacunar cryptogenic cerebral ischemia in young adults. Although the first clinical trials did not show a significant superiority of PFO closure in the secondary prevention of cerebral ischemia as compared with standard antithrombotic treatment, six subsequent randomized clinical trials (CLOSURE I, PC Trial, RESPECT, CLOSE, REDUCE, and DEFENSE-PFO) performed in a sample of cryptogenic stroke in patients aged 60 years or younger provided evidence of a significant reduction of recurrent cerebral ischemia after percutaneous PFO closure. However, the use of percutaneous PFO closure cannot be generalized to the entire population of patients with cerebral ischemia and PFO, but it is indicated in highly selected patients with non-lacunar cryptogenic cerebral infarction with a large right-to-left shunt, an atrial septal aneurysm and no evidence of atrial fibrillation, as well as in association with antithrombotic treatment for an optimal secondary prevention of cerebral ischemia.