Integrin α2β1 is the principal adhesive receptor for collagen but platelets also adhere through glycoprotein VI (GPVI). Integrin αIIbβ3 may augment platelet adhesion. We have shown that disulfide exchange is necessary for platelet adhesion to fibrinogen, fibronectin, and collagen. However 2 questions remained: (1) Can activated αIIbβ3 explain the observed role of disulfide exchange in adhesion to collagen, or is this role common to other integrins? (2) Is disulfide dependence specific to the integrin receptors or shared with GPVI? To discriminate adhesive functions of α 2β1 from those of αIIbβ 3 we used Glanzmann platelets and αIIbβ 3-specific antibodies applied to normal platelets. To resolve adhesive events mediated by α2β1 from those of GPVI we used synthetic peptides specific to each receptor. We addressed direct integrin ligation using purified α2β1 and recombinant I domain. We observed the following: adhesion to the α 2β1-specific peptide was disulfide-exchange dependent and protein disulfide isomerase (PDI) mediated; membrane-impermeant thiol blockers inhibited α2β1, but not GPVI mediated, adhesion; direct blockade of PDI revealed that it is involved in adhesion through α2β1 but not GPVI; and purified α2β1, but not recombinant I domain, depended on free thiols for ligation. These data suggest that the enzymatically catalyzed adhesion-associated reorganization of disulfide bonds is common to members of the integrin family and specific to this family.