Metargidin (ADAM-15) is a type I transmembrane glycoprotein belonging to the ADAM (A Disintegrin and Metalloprotease Domain) family of proteins and is widely expressed in different tissues and cell types. Members of this family contain an amino-terminal metalloprotease domain followed by a disintegrin domain, a cysteine-rich region and a membrane proximal EGF-like domain. The disintegrin domain of metargidin contains an RGD tripeptide sequence, suggesting that it may potentially interact with the integrin family of proteins. Here we identify integrin ligands for metargidin on haemopoietic cells, by using a chimeric protein containing the extracellular domain of metargidin fused to the Fc portion of human IgG. Binding activity to a panel of human cell lines was analysed by solid-phase cell-adhesion assays. Metargidin bound to a monocytic cell line, U937, and a T cell line, MOLT-4, in a specific manner. Adhesion was divalent cation- and temperature-dependent and strongly enhanced by Mn²⁺, all features of integrin-mediated binding. Using a panel of anti-integrin antibodies we show that α_vβ₃ is a ligand for metargidin on U937 cells. In contrast, for MOLT-4 cells, the integrin α₅β₁ contributes to cell binding. Adhesion was mediated by the disintegrin domain of metargidin as RGD-based peptides inhibited cell binding to both cell lines. The specificity of the interaction between both α_vβ₃ and α₅β₁ and metargidin was further confirmed by solid-phase adhesion assays using purified recombinant integrins. These results together indicate that metargidin can function as a cell adhesion molecule via interactions with α_vβ₃ and α₅β₁ integrins.