Inhibition of platelet aggregation following aspirin ingestion is thought to be overcome by the presence of a small minority of uninhibited platelets. Indeed, it is often quoted that more than 95% of platelets must be inhibited by aspirin for full anti-thrombotic protection.1 ,2 Aspirin is an irreversible inhibitor of platelet cyclooxygenase, while the thienopyridines, notably clopidogrel and prasugrel, are irreversible blockers of platelet P2Y12 receptors. In analogy to the effects of aspirin, we have investigated the relationships between the proportion of P2Y12 inhibited platelets and aggregation responses, using the agonists ADP, U46619, TRAP-6 amide and collagen. Platelet rich plasma obtained from healthy volunteers was incubated with either prasugrel-active metabolite (PAM; 3 μM) or vehicle. After washing, different combinations of PAM- and vehicle-treated platelets were transferred to 96-well plates containing fibrinogen (10 μM), CaCl2 (2 μM) and increasing concentrations of ADP, U46619, TRAP-6 amide or collagen. To follow platelet aggregation, absorbance at 595 nm was measured over 16 min of vigorous shaking. In contrast to studies with aspirin, in this in vitro study we have found a linear relationship between the proportion of P2Y12 receptor uninhibited platelets and aggregation in responses to ADP, U46619 and TRAP-6 amide. As P2Y12 receptor antagonists are almost always used in conjunction with aspirin for anti-thrombotic protection this suggests a complex relationship between proportions of uninhibited platelets and platelet responsiveness which demands further examination, particularly with regard to at risk patient groups.