Background: In patients with chronic coronary disease (CCD), it is unclear whether the use of potent P2Y12 inhibitors (ticagrelor or prasugrel) offers advantages to clopidogrel when prescribed in conjunction with aspirin in patients undergoing percutaneous coronary intervention (PCI) with atherectomy. Methods: Consecutive patients undergoing PCI with atherectomy for CCD at a tertiary care center between January 2011 to December 2020 were included. Patients discharged on ticagrelor or prasugrel were compared to patients on clopidogrel. The primary outcome was a composite of death or myocardial infarction (MI), secondary outcomes included individual components of the primary outcome, stroke, major bleeding, and target vessel revascularization at 1 year. Adjusted analyses were performed using propensity score stratification. Results: Overall, 3,612 patients undergoing atherectomy were included in the analysis (clopidogrel [70.4%, n= 2,543], ticagrelor/prasugrel [29.5%, n=1,069]). Clopidogrel was prescribed more often in older patients with multimorbid risk factors, whereas ticagrelor/prasugrel was used more in patients with greater anatomical and procedural complexity. There was an increase in the use of potent antiplatelet agents over time (p<0.001). At 1-year follow-up, the primary outcome was observed in 5.2% and 4.0% of those taking clopidogrel and ticagrelor/prasugrel, respectively (adjusted hazard ratio (AHR) 0.87, 95% CI 0.58 – 1.3, p = 0.50). There were no significant differences in the rate of bleeding (5.5% vs 3.7%, AHR 0.98, 95% CI 0.66 - 1.46, p = 0.92) or other secondary outcomes between the two groups. Conclusion: The use of clopidogrel was associated with comparable ischemic and bleeding outcomes compared to ticagrelor/prasugrel in patients with CCD undergoing PCI with atherectomy.