High on-treatment platelet reactivity (HTPR) despite use of P2Y12 antagonists is associated with adverse cardiac events. The long-term variability in response to prasugrel and ticagrelor is unclear. Our aim was to assess residual platelet reactivity (PR) and rates of HTPR during treatment with prasugrel versus ticagrelor in patients with myocardial infarction (MI). 114 patients with MI treated with percutaneous coronary intervention (PCI) were included. Sixty-two patients were treated with prasugrel (mean age 58 ± 8 years, 21 % women, 29 % diabetes), and 52 patients with ticagrelor (mean age 63 ± 9, 19 % women, 37 % diabetes). Patients were tested for PR at 2-4 days and 30 days post-PCI, using the VerifyNow P2Y12 assay and the multiple-electrode aggregometry. Our results show a higher residual PR in patients treated with prasugrel than those treated with ticagrelor (VerifyNow: 65.4 ± 60.6 vs. 26.0 ± 24.2 P2Y12 reaction units, p < 0.001 at 2-4 days, and 67.3 ± 62.5 vs. 21.1 ± 26.1, p < 0.001 at follow-up). HTPR rates were higher in the prasugrel group (8.1-11.3 % vs. none with ticagrelor in the early test, and 8.7-10.9 % vs. none with ticagrelor at follow-up). In conclusion, in patients with MI undergoing PCI, treatment with ticagrelor resulted in greater platelet inhibition and lower HTPR rates compared with prasugrel, up to 30 days after the event.