BM‐40 (also known as SPARC or osteonectin) is an anti‐adhesive secreted glycoprotein involved in tissue remodelling. Apart from an acidic N‐terminal segment, BM‐40 consists of a follistatin‐like (FS) domain and an EF‐hand calcium‐binding (EC) domain. Here we report the crystal structure at 3.1 Å resolution of the FS–EC domain pair of human BM‐40. The two distinct domains interact through a small interface that involves the EF‐hand pair of the EC domain. Residues implicated in cell binding, inhibition of cell spreading and disassembly of focal adhesions cluster on one face of BM‐40, opposite the binding epitope for collagens and the N‐linked carbohydrate. The elongated FS domain is structurally related to serine protease inhibitors of the Kazal family. Notable differences are an insertion into the inhibitory loop in BM‐40 and a protruding N‐terminal β‐hairpin with striking similarities to epidermal growth factor. This hairpin is likely to act as a rigid spacer in proteins containing tandemly repeated FS domains, such as follistatin and agrin, and forms the heparin‐binding site in follistatin.