Integrins are a large family of cell surface receptors that are involved in a wide range of biological processes. The integrin alpha(IIb)beta3 (glycoprotein IIb-IIIa) is a major platelet glycoprotein heterodimeric receptor that mediates platelet aggregation and is currently a target for pharmaceutical intervention. Ligand binding to the receptor has been shown to induce conformational changes by physical methods and the exposure of neoepitopes (the ligand-induced binding sites). Here we show that the antagonist XP280 induces a conformation that is stable to treatment with SDS and that the protein retains this conformation for several days even after dissociation of the inhibitor. These ligand-induced conformational changes take place with purified protein and on intact platelets. They are competable with an RGDS peptide and are stable to reduction but not boiling or treatment with EDTA. The retention of an altered conformation in the absence of the ligand implies the possibility of ligand-induced alteration of biological function even in the absence of ligand. Finally, similar behavior is observed with the integrin alpha(v)beta3, suggesting that access to SDS stable conformations may be conserved throughout the integrin superfamily. The unusual stability, long-lived nature, and potential generality of these conformations could have profound implications for integrin biology.