The human plasma glycoprotein Factor VIII/von Willebrand factor (vWF) binds specifically and with high affinity to sulfatides (galactosylceramide-I3-sulfate). vWF does not bind to gangliosides, neutral glycolipids, phospholipids, or cholesterol 3-sulfate. Although the largest oligomers of vWF bind preferentially to sulfatides, vWF monomers and dimers also bind but with reduced affinity. vWF binding is inhibited at high ionic strength or low pH, by some sulfated polysaccharides and by antibodies to vWF. Binding of vWF to sulfatides is probably responsible for its agglutination of aldehyde-fixed erythrocytes and may play a role in vWF-induced platelet adhesion or platelet aggregation.