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Glycoprotein IIb/IIIa inhibitors (GPIs) have been regarded as an adjuvant regimen to deal with no-reflow. However, whether intralesional (IL) administration of GPIs improves myocardial reperfusion without increasing bleeding in patients with acute coronary syndrome (ACS) compared with intracoronary (IC) administration has not been well addressed. Our meta-analysis aimed to evaluate the efficacy and safety of IL versus IC administration of GPIs for patients with ACS during percutaneous coronary intervention.We systematically searched Medline, Embase, the Cochrane Central Register of Controlled Trials, and Cambridge Scientific Abstracts from January 2007 to May 2017. Thrombolysis in Myocardial Infarction (TIMI) 3 flow, corrected TIMI frame count (CTFC), and complete ST-segment resolution (>70%) were selected as the primary outcomes. Major adverse cardiac events (MACEs) were the secondary outcome, and major bleeding complications were the safety outcome. Data analysis was conducted using the Review Manager 5.3 software.Six randomized controlled trials were included in our meta-analysis. Compared with IC, IL obtained better results in terms of TIMI grade 3 flow [odds ratio (OR) 2.29; 95% confidence intervals (CIs) 1.31–4.01; P = .004], CTFC [weighted mean difference (WMD) -4.63; 95% CI -8.82 to -0.43; P= .03], and complete ST-segment resolution (OR 1.55; 95% CI 1.12–2.14; P = .008). There was a trend toward decreased MACE in the IL administration groups, which was not of statistical significance (OR 0.63; 95% CI 0.30–1.31; P = .22). No significant difference was found between the two groups in terms of in-hospital major bleeding events (OR 2.52; 95% CI .66 to 9.62; P = .18).IL administration yielded favorable outcomes in terms of myocardial tissue reperfusion as evidenced by the improved TIMI flow grade, CTFC, complete ST-segment resolution, and decreased MACE without increasing in-hospital major bleeding events. The IL administration of GPIs can be recommended as the preferred regimen to guard against no-reflow.