Aim The aim of the present study was to investigate the patterns of platelet reactivity and discriminators of therapeutic response to dual antiplatelet therapy (DAPT) with aspirin and ticagrelor or prasugrel in patients with acute coronary syndrome (ACS). Design In this multicentre prospective observational study, 492 patients with ACS were enrolled. Platelet aggregation was determined by multiple electrode aggregometry after stimulation with adenosine diphosphate (ADP) or arachidonic acid (AA) as agonists in the maintenance phase of treatment with prasugrel or ticagrelor. Results Age emerged as the strongest variable influencing aspirin response status: The mean AA‐induced platelet aggregation in patients <49 years of age was 49% higher than in those >49 years (13.1 U vs 8.8 U; P = 0.011). The second strongest discriminator of aspirin response was sex: Male patients had a 40% higher AA‐induced platelet aggregation values than female patients (9.5 U vs 6.8 U; P = 0.026). Platelet count emerged as the only variable influencing ADP antagonists response status showing that patients with platelet count >320 g/L displayed higher ADP‐induced platelet aggregation. About 12% of patients had high on‐treatment platelet reactivity (HTPR) to aspirin, 3% and 4% a HTPR to prasugrel and ticagrelor, respectively, and only 2% displayed HTPR to dual antiplatelet therapy. Conclusion When potent platelet inhibitors as prasugrel and ticagrelor are administered with aspirin, HTPR to DAPT plays only a marginal role.