Newly produced platelets are present in the acute phase of ST-elevation myocardial infarction (STEMI). This may influence the antiplatelet effect of aspirin and clopidogrel administered prior to primary percutaneous coronary intervention (PPCI). The aims of this study were to investigate the antiplatelet effect of aspirin and clopidogrel and evaluate platelet turnover in the acute phase of STEMI compared to a stable phase 3 months later. In this observational follow-up study on 48 STEMI patients transferred for PPCI, loading doses of aspirin (300 mg) and clopidogrel (600 mg) were given orally in the ambulance. Blood samples were obtained immediately prior to PPCI, at 4 and 12 hours after administration of bolus doses and at follow-up after 3 months. Residual platelet aggregation was evaluated by Multiplate® and VerifyNow® aggregometry. Platelet turnover was evaluated by automated flow cytometry. In the acute phase of STEMI at the time of PPCI, residual platelet aggregation was significantly higher prior to PPCI compared to 4 and 12 hours after loading doses of aspirin and clopidogrel and 3 months later (p-values < 0.01). Furthermore, platelet turnover indices (mean platelet volume, immature platelet fraction, and immature platelet count) were increased in the acute phase of STEMI compared to 3 months after PPCI (p-values < 0.0001). In conclusion, residual platelet aggregation was high in the acute phase of STEMI despite dual antiplatelet treatment with aspirin and clopidogrel. Increased platelet turnover may partly explain the reduced efficacy of antiplatelet drugs in the acute phase of STEMI.