Background The safety of administration of tirofiban, a platelet glycoprotein IIb/IIIa inhibitor, followed by a clopidogrel loading dose in clopidogrel-naïve patients undergoing ad-hoc percutaneous coronary intervention (PCI) is not yet clear. Methods In a retrospective observational cohort analysis, clopidogrel-naïve patients undergoing ad-hoc PCI who received a high-dose bolus of tirofiban (25 μg/kg) followed by a 600-mg clopidogrel loading dose (group 1) were compared with patients undergoing elective PCI who were pretreated with clopidogrel (group 2), between September 2014 and October 2021. The primary outcome was major adverse cardiovascular events (MACE) defined as the composite of death, myocardial infarction, stroke, target-lesion revascularisation and bleeding at 30 days. Secondary outcomes were MACE at 7 days and individual components of the primary outcome at 7 and 30 days. Results A total of 1404 patients were included: 432 (31%) in group 1 and 972 (69%) in group 2. Median age was 69 years, and 28% were female. At 7‑day follow-up, MACE occurred in 1.4% in group 1 versus 3.0% in group 2 ( p  = 0.08). 30-day MACE were observed in 1.9% in group 1 and 4.2% in group 2 ( p  = 0.03). Secondary outcomes were comparable between the groups. Cox regression analysis, corrected for baseline differences, revealed no significant difference in the primary outcome (hazard ratio: 1.8; 95% confidence interval: 0.8–3.9). Conclusion Ad-hoc PCI in clopidogrel-naïve patients who were treated with high-dose bolus of tirofiban followed by a clopidogrel loading dose immediately after the procedure appeared to be safe.