We recently demonstrated that blockade of the platelet adhesion receptor glycoprotein (GP) Ibα protects mice from ischemic stroke. Although von Willebrand factor (VWF) is the major ligand for GPIbα, GPIbα can engage other counterreceptors on endothelial cells, platelets, and leukocytes (eg, Mac-1 or P-selectin) potentially involved in stroke outcome. To further analyze whether VWF is of particular relevance for stroke development, VWF^−/− mice underwent 60 minutes of middle cerebral artery occlusion. After 24 hours, VWF^−/− mice had significantly smaller infarctions (P < .05) and less severe neurologic deficits (P < .01) compared with controls. This effect was sustained after 1 week, and intracranial bleeding was absent in VWF^−/− mice as revealed by serial magnetic resonance imaging. Hydrodynamic injection of a VWF-encoding plasmid restored the susceptibility for stroke in VWF^−/− mice. This study indicates that VWF is critically involved in cerebral ischemia. Hence, targeted inhibition of the GPIbα-VWF pathway might become a promising therapeutic option.