The studies reported present evidence that a free or intact sulfhydryl group is involved in platelet adhesion to connective tissue. Exposure of platelets to the readily penetrating sulfhydryl inhibitors NEM or PHMB immediately blocks their ability to adhere to connective tissue. PHMBS, which penetrates platelet membrane very slowly, produces an inhibitory effect only after prolonged incubation. These observations suggest that an SH-containing substrate affecting the adhesion reaction is probably located beneath the plasma membrane of the platelet.