The syndecan family of cell surface proteoglycans regulates cell adhesion and growth factor signaling by binding components of the extracellular matrix and growth factors. To date, all known ligand interactions are via the covalently attached glycosaminoglycan chains. To assay for potential extracellular interactions via the core proteins directly, the recombinant extracellular domain of syndecan-4 (S4ED), one of the four syndecan family members, was tested as a substratum for the attachment of mammalian cells. Human foreskin fibroblasts bind to mouse S4ED, and both mouse and chicken S4ED can block this binding, with 50% inhibition observed between 0.1 and 1 x 10(-7) M. The extracellular domain of another syndecan family member, syndecan-1, fails to compete for cell binding to mouse S4ED. Amino acids 56-109 of the 120-amino acid mouse S4ED compete fully, suggesting that the cell binding domain is within this region. The ability of syndecan-4 to interact with molecules at the cell surface via its core protein as well as its glycosaminoglycan chains may uniquely regulate the formation of cell surface signaling complexes following engagement of this proteoglycan with its extracellular ligands.