Aims: In the HORIZONS-AMI trial, bivalirudin compared to unfractionated heparin (UFH) plus a glycoprotein IIb/IIIa inhibitor (GPI) improved net clinical outcomes in patients undergoing primary percutaneous coronary intervention (PCI) at the cost of an increased rate of acute stent thrombosis. We sought to examine whether these effects are dependent on time to treatment. Methods and results: The interaction between anticoagulation regimen and symptom onset to first balloon inflation time (SBT) on the 30-day and three-year rates of major adverse cardiac events (MACE) was examined in 3,199 randomised patients according to SBT ≤3 hours versus >3 hours. Among patients with an SBT ≤3 hours, bivalirudin resulted in higher 30-day rates of MACE compared to UFH plus a GPI. Nonsignificant differences were observed in patients with an SBT >3 hours. Similar results were found for MACE at three years and stent thrombosis and reinfarction at 30 days and three years. By multivariable analysis, bivalirudin was an independent predictor of MACE at 30 days and three years in patients with an SBT ≤3 hours, but not in patients with SBT >3 hours. Conclusions: Bivalirudin compared to UFH plus a GPI is associated with an increased rate of stent thrombosis and MACE in patients with short SBTs, but not in those with longer SBTs.