Background: Early treatment with a potent oral platelet P2Y ₁₂ inhibitor is recommended in patients presenting with ST-segment–elevation myocardial infarction scheduled to undergo primary percutaneous coronary intervention (pPCI). The impact on coronary reperfusion of crushed P2Y ₁₂ inhibitor tablets, which lead to more prompt and potent platelet inhibition, is unknown. Methods: We conducted a randomized controlled, multicenter trial in the Netherlands, enrolling patients with ST-segment–elevation myocardial infarction scheduled to undergo pPCI. Patients were randomly allocated to receive in the ambulance, before transfer, a 60-mg loading dose of prasugrel either as crushed or integral tablets. The independent primary end points were thrombolysis in myocardial infarction (TIMI) 3 flow in the infarct-related artery at initial coronary angiography, and complete (≥70%) ST-segment resolution 1 hour after pPCI. The safety end points were TIMI major and Bleeding Academic Research Consortium ≥3 bleedings. Secondary end points included platelet reactivity and ischemic outcomes. Results: A total of 727 patients were assigned to either crushed or integral tablets of prasugrel loading dose. The median time from study treatment to wire-crossing during pPCI was 57 (47–70) minutes. The primary end point TIMI 3 flow in the infarct-related artery before pPCI occurred in 31.0% in the crushed group versus 32.7% in the integral group (odds ratio, 0.92 [95% CI, 0.65–1.30], P =0.64). Complete ST-segment resolution 1 hour after pPCI was present in 59.9% in the crushed group versus 57.3% in the integral group (odds ratio, 1.11 [95% CI, 0.78–1.58], P =0.55). Platelet reactivity at the beginning of pPCI, measured as P2Y ₁₂ reactivity unit, differed significantly between groups (crushed, 192 [132–245] versus integral, 227 [184–254], P ≤0.01). TIMI major and Bleeding Academic Research Consortium ≥3 bleeding occurred in 0% in the crushed group versus 0.8% in the integral group, and in 0.3% in the crushed group versus 1.1% in the integral group, respectively. There were no differences observed between groups regarding ischemic events at 30 days. Conclusions: Prehospital administration of crushed prasugrel tablets does not improve TIMI 3 flow in the infarct-related artery before pPCI or complete ST-segment resolution 1 h after pPCI in patients presenting with ST-segment–elevation myocardial infarction scheduled for pPCI. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03296540.