Glycoprotein IIb/IIIa receptor inhibitors (GPIs) have been widely adopted as an adjuvant regimen during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction, but whether intracoronary administration of these potent antiplatelet agents conveys better efficacy and safety over the intravenous route has not been well addressed. A meta-analysis was performed by a systematic search of the published research for randomized controlled trials comparing intracoronary versus intravenous administration of GPIs in patients with ST-segment elevation myocardial infarction. Eight studies involving 686 patients in the intracoronary arm and 660 in the intravenous arm met the inclusion criteria. Postprocedural Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow (odds ratio [OR] 1.46, 95% confidence interval [CI] 1.08 to 1.98, p <0.05) and myocardial reperfusion grade 2 or 3 (OR 1.78, 95% CI 1.29 to 2.46, p <0.001) were markedly more often achieved in patients who received intracoronary boluses of GPIs than those receiving the intravenous strategy. Intracoronary administration resulted in a reduced incidence of mortality (OR 0.44, 95% CI 0.21 to 0.92, p <0.05), target vessel revascularization (OR 0.53, 95% CI 0.29 to 0.99, p <0.05), and the composite end point of major adverse cardiac events (OR 0.48, 95% CI 0.31 to 0.76, p <0.005) at 30-day follow-up. No significant difference was found in terms of major or minor bleeding (OR 1.14, p = 0.71, and OR 0.86, p = 0.47 respectively). In conclusion, intracoronary administration of GPIs yielded favorable outcomes in postprocedural blood flow restoration and 30-day clinical prognosis in patients with ST-segment elevation myocardial infarction. The intracoronary use of GPIs can be recommended as a preferred regimen during primary percutaneous coronary intervention.