We assessed prospectively the association between occurrence of post-discharge non–CABG-related TIMI major and minor bleedings and post treatment platelet reactivity in patients with Non ST Elevation Acute Coronary Syndrome (NSTE ACS). 597 consecutive patients admitted with NSTE ACS were prospectively included. Between hospital discharge and one month follow-up, we observed 16 (2.7%) non–CABG-related TIMI hemorrhagic complications including 5 (0.84%) major and 11 (1.8%) minor bleeds. Patients with bleeding had significantly lower post treatment values of ADP-induced aggregation (43±14% versus. 56±19%, P=0.002) and platelet reactivity index VASP (43±14% versus 54±23%; P=0.04) and a trend for lower values of arachidonic acid-induced aggregation (2.4±5.4 versus 13±21; P=0.27). After stratification by quartiles based on post treatment ADP-induced platelet aggregation, we identified patients in the first quartile as hyper-responders with very low post treatment platelet reactivity, below <40%. The risk of TIMI major and minor bleeding was significantly higher in the first quartile of hyper-responders than in the others quartiles: 10 (6.6%) versus 6 (1.4%), p=0.001. Our results suggest that assessment of post treatment platelet reactivity might be used to detect hyper responders to antiplatelet therapy with higher risk of non-CABG related bleedings and tailor antiplatelet therapy according to both ischemic and bleeding risk.