The platelet integrin α_IIbβ₃ is essential for hemostasis and thrombosis through its binding of adhesive plasma proteins. We have determined crystal structures of the α_IIbβ₃ headpiece in the absence of ligand and after soaking in RUC-1, a novel small molecule antagonist. In the absence of ligand, the α_IIbβ₃ headpiece is in a closed conformation, distinct from the open conformation visualized in presence of Arg-Gly-Asp (RGD) antagonists. In contrast to RGD antagonists, RUC-1 binds only to the α_IIb subunit. Molecular dynamics revealed nearly identical binding. Two species-specific residues, α_IIb Y190 and α_IIb D232, in the RUC-1 binding site were confirmed as important by mutagenesis. In sharp contrast to RGD-based antagonists, RUC-1 did not induce α_IIbβ₃ to adopt an open conformation, as determined by gel filtration and dynamic light scattering. These studies provide insights into the factors that regulate integrin headpiece opening, and demonstrate the molecular basis for a novel mechanism of integrin antagonism.