OBJECTIVE: Aberrant blood-brain barrier (BBB) permeability is a hallmark pathology of many central nervous system diseases. von Willebrand factor (VWF) is stored in endothelial Weibel-Palade bodies from where it is released on activation into plasma and basement membrane. The role of VWF in endothelial homeostasis is unclear. The goal of this study was to assess the role of VWF in disease models associated with increased BBB permeability. APPROACH AND RESULTS: We did not find any differences in BBB permeability to Evans blue dye at baseline between wild-type and VWF(-/-) animals. We next used 2 models presenting with increased BBB permeability, hypoxia/reoxygenation and pilocarpine-induced status epilepticus, to assess the response of VWF(-/-) animals. In both models, VWF(-/-) mice maintained a tighter BBB than wild-type mice. VWF(-/-) mice fared worse in both conditions, with ? 100% of VWF(-/-) mice dying within 120 minutes after pilocarpine administration, whereas >80% of wild-type animals survived. Investigation into the status of tight junction proteins revealed that VWF(-/-) mice expressed more claudin-5 at baseline. In vitro work confirmed that the presence of subendothelial VWF is inhibitory to claudin-5 expression. CONCLUSIONS: VWF deficiency confers partial preservation of BBB integrity after hypoxia/reoxygenation and seizures. Surprisingly, this decrease in BBB permeability did not result in protection of animals because they demonstrated more severe pathology in both models compared with wild-type animals. These data suggest that a rigid BBB is detrimental (to the organism) during certain disease states and that VWF release may provide desired flexibility under stress.