Background: The latest guidelines considered glycoprotein IIb/IIIa inhibitors (GPI) as a bailout strategy in selected situations in patients presented with acute ST ‌segment elevation myocardial infarction (STEMI), however, they did not recommend route of administration over another, and did not correlate it to infarct size. Infarct size correlates generally with prognosis following acute myocardial infarction and reduction in infarct size can boost clinical outcomes and decrease rate of heart failure hospitalization. Objective: To evaluate intracoronary vs intravenous use of tirofiban on reduction of infarct size in STEMI treated with primary percutaneous coronary intervention (PCI). Patients and methods: Between February, 2018, and October, 2019, one hundred patients presented within 6 hours of anterior STEMI undergoing primary PCI after exclusion of rescue PCI, thrombolysis in myocardial infarction (TIMI) flow less than II post PCI, previous myocardial infarction (MI), stent thrombosis, previous coronary artery bypass graft, significant left main occlusion, pulmonary edema and cardiogenic shock.      Infarct size was assessed 1 month after randomization by single photon emission computed tomography (SPECT) and Major adverse cardiovascular events (MACE) during hospital stay (cardiac death, myocardial infarction or stroke), heart failure and bleeding. Results: Patients randomized to intracoronary tirofiban compared with intravenous tirofiban had a significant decrease in the primary end point of infarct size (mean± SD, 14.46%± 7.79% vs 18.06% ± 7.83%). Also associated with lower incidence of heart failure (16% vs 34%). There were no significant differences in any of the MACE or bleeding between the randomized groups at 30 days. Conclusions: In patients with anterior STEMI presenting early after symptom onset, intracoronary tirofiban administration when compared to intravenous route during primary PCI resulted in infarction size reduction and lower heart failure incidence mainly driven by enhanced left ventricular systolic function however, no distinction between two strategies on MACE or bleeding risk.