The identification of common domains among different proteins is of great interest at present. We have found that a cysteine-rich domain in thrombospondin, also present in types I and III procollagen alpha 1 chains, is related to two internally homologous domains in von Willebrand factor. In the four proteins these domains are similar in length (64-74 residues) and have nine invariant cysteines, some of which form intramolecular disulfide bonds. The structural and functional similarities of this domain in the four kinds of proteins, and its correspondence in procollagen to an exon, support our hypothesis of a common origin for the domain.