Von Willebrand factor (vWF) binding to platelets under high fluid shear is an important step regulating atherothrombosis. We applied light and small-angle neutron scattering to study the solution structure of human vWF multimers and protomer. Results suggest that these proteins resemble prolate ellipsoids with radius of gyration (Rg) of ~75nm and ~30nm for multimer and protomer respectively. The ellipsoid major and minor axis radii were of length ~175nm and ~28nm for multimers, and ~70nm and 9.1nm for protomers. The multimer was organized into substructural domains at length scales indicative of the entire protein itself (75nm), elements of the protomer quarternary structure (16nm) and individual functional domains (4.5nm). Individual domains of 4.5nm were also observed in the protomer. Amino acids occupy only ~2% of the multimer and protomer volume, compared to 98% for serum albumin and 35% for fibrinogen. vWF treatment with Guanidine·HCl, which increases vWF susceptibility to proteolysis by ADAMTS-13, causes local structural changes at length scales<10nm without altering protein Rg. Treatment of multimer but not protomer-vWF with random homobifunctional linker BS3, prior to reduction of inter-monomer disulfide linkages and western blotting reveals a pattern of dimer and trimer units that indicate the presence of stable inter-monomer non-covalent interactions within the multimer. Overall, we demonstrate for the first time that the vWF solution structure is stabilized by non-covalent interactions between different monomer units. Local, and not large scale, changes in multimer conformation are sufficient for ADAMTS-13 mediated proteolysis. Possible functional consequences of non-covalent protein interactions on vWF function during thrombosis will be discussed.