The platelet fibrinogen receptor, integrin α_IIbβ₃, is a noncovalent heterodimer of glycoproteins IIb and IIIa. This work was aimed at elucidating the role played by the carboxy-terminal extracellular, trans-membrane, and cytoplasmic regions of the glycoprotein β₃ in the formation of functional complexes with α subunits. Progressive carboxy-terminal deletions of β₃ revealed that surface exposure of α_IIbβ₃ or α_vβ₃ could not occur in the absence of the transmembrane domain of β₃. In contrast, internal deletions 616 to 690 of the carboxy-terminal regions of the β₃ ectodomain led to surface exposure of constitu tive active receptors in CHO cells, as indicated by the enhanced rate of cell adhesion to immobilized ligands and spontaneous binding to soluble fibrinogen or activation-dependent antibody PAC-1. The functional analysis of cysteine mutations within the 616 to 690 region of β₃ or chimeric β₃-β₇ subunits revealed that disruption of the C663-C687 disulfide bridge endows constitutive activity to the α_IIbβ₃ receptor. It is concluded that the carboxy-terminal tail of the β₃ ectodomain, so-called β tail domain (βTD), is not essential for cell surface expression of β₃ receptors. However, a basal, nonactivated, low ligand-affinity state of the β₃ integrins demands a normal conformation of this domain. (Blood. 2003;102:2491-2497)