An integrin found on platelets, α_IIbβ₃ mediates platelet aggregation, and α_IIbβ₃ antagonists are effective antithrombotic agents in the clinic. Ligands bind to integrins in part by coordinating a magnesium ion (Mg²⁺) located in the β subunit metal ion–dependent adhesion site (MIDAS). Drugs patterned on the integrin ligand sequence Arg-Gly-Asp have a basic moiety that binds the α_IIb subunit and a carboxyl group that coordinates the MIDAS Mg²⁺ in the β₃ subunits. They induce conformational changes in the β₃ subunit that may have negative consequences such as exposing previously hidden epitopes and inducing the active conformation of the receptor. We recently reported an inhibitor of α_IIbβ₃ (RUC-1) that binds exclusively to the α_IIb subunit; here, we report the structure-based design and synthesis of RUC-2, a RUC-1 derivative with a ~100-fold higher affinity. RUC-2 does not induce major conformational changes in β₃ as judged by monoclonal antibody binding, light scattering, gel chromatography, electron microscopy, and a receptor priming assay. X-ray crystallography of the RUC-2–α_IIbβ₃ headpiece complex in 1 mM calcium ion (Ca²⁺)/5 mM Mg²⁺ at 2.6 Å revealed that RUC-2 binds to α_IIb the way RUC-1 does, but in addition, it binds to the β₃ MIDAS residue glutamic acid 220, thus displacing Mg²⁺ from the MIDAS. When the Mg²⁺ concentration was increased to 20 mM, however, Mg²⁺ was identified in the MIDAS and RUC-2 was absent. RUC-2’s ability to inhibit ligand binding and platelet aggregation was diminished by increasing the Mg²⁺ concentration. Thus, RUC-2 inhibits ligand binding by a mechanism different from that of all other α_IIbβ₃ antagonists and may offer advantages as a therapeutic agent.