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Background: To determine whether intracoronary pro-urokinase or tirofiban improves myocardial reperfusion during primary percutaneous coronary intervention (PCI) for acute ST-segment elevation myocardial infarction (STEMI).Methods: The study included patients with acute STEMI presenting within 12 h of symptoms at 11 hospitals in China between November 2015 and July 2017. Patients were randomized to receive selective intracoronary infusion of recombinant pro-urokinase (20 mg), tirofiban (10 μg/kg), or saline (20 mL) proximal to the infarct-related lesion over a 3-min period before stent implantation during primary PCI. The primary outcome was final corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC) after PCI.Results: This study included 345 patients. Initial angiography identified a high-grade thrombus (TIMI 4–5) in 80% of patients. Final CTFC after PCI was significantly lower in the pro-urokinase (P < 0.001) and tirofiban (P < 0.001) groups than in the saline group and similar between the pro-urokinase and tirofiban groups (P > 0.05). The pro-urokinase (P = 0.008) and tirofiban groups (P = 0.022) had more complete ST-segment resolution at 2 h and lower peak creatine kinase-MB levels after PCI than the saline group (P = 0.006 and P = 0.023). The 30-day incidence of major adverse cardiac events was 4.5% in the pro-urokinase group, 3.4% in the tirofiban group, and 2.6% in the saline group. The incidence of in-hospital TIMI major bleeding events was low and comparable between groups.Conclusions: Adjunctive intracoronary pro-urokinase or tirofiban given before stent implantation during primary PCI improves myocardial reperfusion without increasing the incidence of major bleeding events.