Background: ST-segment elevation myocardial infarction (STEMI) is a clinical syndrome with high mortality. The main purpose of STEMI treatment is to achieve optimal revascularization for tissue perfusion. Besides the innovations in revascularization strategies, developments in antithrombotic therapy resulted in a significant reduction in STEMI-related mortality. Reperfusion can be demonstrated by resolution of ST-segment elevation (STR), TIMI frame count (TFC), and myocardial blush grade (MBG). Aim of the study: In our study, we investigated the effects of P2Y12 inhibitors clopidogrel, prasugrel, and ticagrelor on reperfusion parameters such as TFC, MBG, and STR, after primary percutaneous coronary intervention (pPCI) in STEMI. Material and Methods: The study was a retrospective analysis of STEMI patients who underwent successful pPCI. A total of 120 patients were included in the study as 3 equal groups according to the type of P2Y12 inhibitor administered in loading dose in the acute phase, and reperfusion parameters were compared between the groups. Results: There was no statistically significant difference between the groups in terms of baseline demographic, clinical, and angiographic parameters. Evaluation of reperfusion parameters indicated that STR, MBG, angina relief after pPCI and corrected TFC (cTFC) were significantly different between the groups (p <0.05). In post-hoc analysis, the percentage of change in STR, MBG, angina relief after pPCI, and cTFC was significantly higher in the prasugrel group (p <0.017). Conclusion: In STEMI patients undergoing pPCI, the analysis of tissue level reperfusion parameters indicates a superior effect of prasugrel compared with other P2Y12 inhibitors used to achieve reperfusion.