Background <p>Chronic total occlusion (CTO) affects 15–25% of patients undergoing coronary angiography, and successful percutaneous coronary intervention (PCI) can improve ischemia, angina symptoms, and overall quality of life. However, CTO-PCI is a complex procedure with higher risks of acute thrombosis, restenosis, and long-term thrombosis due to factors such as longer lesion length, calcification, and the need for more stents. Dual antiplatelet therapy (DAPT) is essential after PCI, but the optimal regimen for CTO, particularly in patients with chronic coronary syndrome, remains under debate. Although more potent P2Y12 inhibitors such as ticagrelor may offer benefits in some cases, recent studies have shown mixed results.</p> Objective <p>This study aimed to assess the effect of potent DAPT on long-term outcomes in patients with CTO undergoing retrograde PCI.</p> Method <p>We conducted a retrospective analysis of 836 consecutive patients who underwent elective retrograde CTO-PCI at a single center between January 2011 and April 2023. We compared patient and lesion characteristics, procedural details and results, and long-term outcomes between patients who received ticagrelor and those who received clopidogrel after retrograde CTO-PCI.</p> Result <p>Clinical follow-up was available in 767 (91.2%) patients, with a median follow-up of 1041 days (range 531–1511). The risk of major adverse cardiovascular events was significantly lower in patients receiving ticagrelor than in those receiving clopidogrel (8.8% vs. 18.5%, <i>p</i> = 0.005), primarily due to reductions in all-cause mortality (1.9% vs. 8.1%, <i>p</i> = 0.009) and cardiac death (0.6% vs. 5.8%, <i>p</i> = 0.012).</p> Conclusion <p>DAPT with ticagrelor may represent a safe and efficient management strategy for patients undergoing retrograde CTO-PCI.</p>