Von Willebrand factor (VWF) is a large soluble protein found in human blood, with molecular weight (MW) ranging from 500kDa for dimeric/protomer protein to >10,000kDa for linear multimers. The binding of this protein to blood platelets under high fluid shear is an important step regulating atherothrombosis. We applied small-angle neutron scattering (SANS) to study in real-time, without fixation or protein-labeling artifacts, the effect of hydrodynamic shear on the solution structure of VWF. To this end, VWF purified from human plasma cryoprecipitate was placed in a quartz couette-shear cell that was aligned in the path of a 0.6nm neutron beam. Application of laminar shear in the range from 300/s-3000/s triggered changes in scattering intensity which are indicative of structural changes in VWF in response to flow. The most prominent changes observed were at small length scale (<10nm) and these are representative of alterations in domain level features within VWF. The data collected did not support the concept that VWF may unravel in response to fluid shear under our experimental conditions. In control runs, neither shearing bovine serum albumin (BSA) nor buffer alone resulted in changes in neutron scattering intensity. Structural changes observed in VWF were not reversible upon shear stoppage. Computational modeling of VWF solution conformation support the concept that fluid shear alters the inter-domain distances within the globular head section of VWF. These domain level changes may be the first step that precedes larger scale structural changes within the protein.