We report a 47-years-old male with ischemic stroke, whose arteriographic and echocardiographic investigations did not reveal any steno-occlusive arterial disease or embolic source from the left cardiac chambers. A transesophageal echocardiogram showed a patent foramen ovale (PFO), whilst laboratory screening for coagulation abnormalities showed heterozygosity for factor V Leiden mutation. The significance of the association of PFO with factor V Leiden mutation is discussed as a possible cause of ischemic stroke through paradoxical embolism from a venous source. The high prevalence of these two conditions in the general population is emphasized and the indication for anticoagulant therapy is discussed.