Platelet activation and aggregation play a major role in thrombosis formation of coronary arteries in patients with Acute Coronary Syndrome (ACS) and is responsible for most ischemic complications during PCI. There is little information on the benefits and side effects of intracoronary and intravenous injection of Eptifibatide, a potent antiplatelet agent; therefore, this study was performed with the aim to compare coronary blood flow velocity by measurement of TIMI frame count. In intravenous versus intracoronary bolus administration of Eptifibatide during PCI in ACS patients. This non-randomized clinical trial study was performed on 103 patients with acute coronary syndromes who referred to the cardiac emergency ward of Ghaem hospital, Mashhad University of Medical Sciences, and were candidates for urgent coronary angiography and PCI. Forty-eight cases received intracoronary bolus Eptifibatide and 55 intravenous Eptifibatide. TIMI Frame Count and Corrected TIMI Frame Count were used to comparing the effect of these two methods on coronary blood flow velocity. Data were analyzed by SPSS software (version 22). To compare the quantitative variables in the two groups, according to the distribution of variables, the t-test was used if it was normal or the Mann-Whitney test was used if it was not normal. A Chi-square test was also used to compare qualitative variables into two groups. P<0.05 was considered statistically significant. Mean of age, gender, and cardiovascular risk factors were similar in the two groups. There was no significant difference in terms of serum Creatine Kinase MB (CKMB) level, Left Ventricular Ejection Fraction (LVEF), coronary artery lesion length, coronary artery diameter, coronary thrombosis, and coronary artery thrombectomy in two groups. Based on Student's t-test, there was no significant difference between mean TIMI Frame Count in different coronary arteries in the intracoronary and intravenous injection groups (In LAD, P=0.518; For LCX, P=0.576; and in RCA, P=0.964). The complications were observed in 11 patients (22.9%) of the intracoronary injection group and 9 (16.4%) of the intravenous injection group; the difference was not significant (P=0.402). The effects and complications of Eptifibatide were not significantly different in Intracoronary and intravenous administration in ACS patients during PCI and at the time of patients' hospitalization.