We pooled available data on follow-up events in patients with patent foramen ovale and cryptogenic stroke to evaluate the net clinical benefit of different therapeutic strategies (percutaneous closure vs antiplatelet vs anticoagulant therapy). MEDLINE/PubMed and Cochrane databases and reviewed cited references to identify relevant studies were used; 3,311 patients from 21 clinical studies, both observational and randomized, with follow-up ≥12 months were overall included. Net clinical benefit was evaluated considering the cumulative incidence of both stroke and/or transient ischemic attack and major bleeding events. Anticoagulant therapy was more effective than antiplatelet therapy in preventing recurrent stroke and/or transient ischemic attack (event rates: 7.7% vs 9.8%, respectively, p = 0.03), but at the price of more than sixfold greater risk of major bleeding (7.1% vs 1.3%; odds ratio 6.49, 95% confidence interval 3.25 to 12.99, p <0.00001). Patent foramen ovale closure was associated over the long term with significant net clinical benefit versus both antiplatelet and anticoagulant therapy; such benefit was driven by 50% relative reduction of stroke and/or transient ischemic attack versus antiplatelet therapy and by 82% relative reduction of major bleeding versus anticoagulant therapy. In conclusion, results of this large study-level meta-analysis may influence practice patterns in patients with patent foramen ovale and cryptogenic stroke; an individualized approach tailored on both the risk of recurrent cerebral events and the bleeding risk should be used to identify the best therapeutic option (percutaneous closure vs antiplatelet therapy vs anticoagulant therapy).