Background and Purpose-Multiple acute ischemic lesions on diffusion-weighted magnetic resonance imaging (DWI-MRI) are thought to be of embolic origin. However, in several patients with multiple ischemic lesions on DWI-MRI, no embolic source was detected, despite a thorough clinical work-up. Stroke etiology in such cases is then classified as cryptogenic. In other patients, a potential embolic source is limited to a patent foramen ovale (PFO) that may act as an embolic source of unsure relevance. We therefore examined the prevalence of the multiple-lesion pattern in patients with cryptogenic stroke compared with patients with PFO. Methods-We screened 650 stroke patients by DWI-MRI. For the subsequent evaluation, we excluded patients with a cardiac embolic source other than PFO, symptomatic carotid artery disease, and other apparent stroke causes, such as dissection or vasculitis, and patients whose diagnostic work-up was incomplete. For the remaining 106 patients, we found DWI lesions in 73, who were subjected to further evaluation. Results-There were no differences in the occurrence of the multiple-lesion pattern in patients with cryptogenic stroke compared with patients with PFO, either for the entire group or for the subgroup of young stroke patients who were < 50 years old. Patients with PFO showed a significantly higher incidence of multiple lesions in the posterior circulation. Conclusions-The multiple-lesion pattern on DWI-MRI is not uncommon, even when extensive testing does not reveal any embolic source. Therefore, it is not possible to discriminate between cryptogenic stroke and stroke from an assumed paradoxical embolism.