The platelet integrin receptor alphaIIbbeta3 plays a critical role in thrombosis and haemostasis by mediating interactions between platelets and several ligands but primarily fibrinogen. It has been shown previously that the YMESRADR KLAEVGRVYLFL (313-332) sequence of the alphaIIb subunit plays an important role in platelet activation, fibrinogen binding and alphaIIbbeta3-mediated outside-in signalling. Furthermore, we recently showed that the 20-residue peptide (20-mer) alphaIIb 313-332, is a potent inhibitor of platelet aggregation and fibrinogen binding to alphaIIbbeta3, interacting with fibrinogen rather than the receptor. In an effort to determine the sequence and the minimum length required for the biological activity of the above 20-mer, we synthesized seven octapeptides, each overlapping by six residues, covering the entire sequence and studied their effect on platelet activation as well as fibrinogen binding to activated platelets. We show for the first time that octapeptides containing the RAD sequence are capable of inhibiting platelet aggregation and secretion as well as fibrinogen binding to the activated alphaIIbbeta3, possibly interacting with the ligand rather than the receptor. This suggests that the RAD sequence, common to all the inhibitory peptides, is critical for their biological activity. However, the presence of the YMES sequence, adjacent to RAD, significantly increases the peptide's biological potency. The development of such inhibitors derived from the 313-332 region of the alphaIIb subunit may be advantageous against the RGD-like antagonists as they could inhibit platelet activation without interacting with alphaIIbbeta3, thus failing to further induce alphaIIbbeta3-mediated outside-in signalling.