The red cell intercellular adhesion molecule‐4 (ICAM‐4) binds to different members of the integrin receptor families. To better define the ICAM‐4 integrin receptor specificity, cell transfectants individually expressing various integrins were used to demonstrate that α_Lβ₂, α_Mβ₂, and α_IIbβ₃ (activated) bind specifically and dose dependently to the recombinant ICAM‐4‐Fc protein. We also show that cell surface ICAM‐4 interacts with the cell surface α_Vβ₃ integrin. In addition, using a α₄β₁ cell transfectant and β₂ integrin‐deficient LAD cells, we show here that ICAM‐4 failed to interact with α₄β₁ even after α₄β₁ activation by phorbol ester or with the monoclonal antibody TS2/16 (+ Mn²⁺). ICAM‐4 amino acids that are critical for α_IIbβ₃ and α_Vβ₃ interaction were identified by domain deletion analysis, site‐directed mutagenesis and synthetic peptide inhibition. Our results provide evidence that the β₃ integrin binding sites encompass the first and second Ig‐like domains of ICAM‐4. However, while the α_IIbβ₃ contact site comprises the ABED face of domain D1 with an extension in the C′‐E loop of domain D2, the α_Vβ₃ contact site comprises residues on both faces of D1 and in the C′‐E loop of D2. These data, together with our previous results, demonstrate that different integrins bind to different but partly overlapping sites on ICAM‐4, and that ICAM‐4 may accommodate multiple integrin receptors present on leukocytes, platelets and endothelial cells.