A new meta-analysis suggests that clopidogrel may be a safer and more effective option than aspirin for patients who have completed dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI). The findings could reshape post-PCI treatment strategies by challenging the long-held dominance of aspirin as the standard maintenance therapy. The systematic review and meta-analysis evaluated data from 4 randomized controlled trials (RCTs) involving 19,554 patients (9,846 were assigned to clopidogrel monotherapy and 9,708 to aspirin monotherapy), after completion of DAPT. The comprehensive search spanned major databases, including MEDLINE, Embase, Scopus, CENTRAL, and ClinicalTrials.gov, up to April 12, 2025. The research analyzed major cardiovascular outcomes, including stroke, myocardial infarction (MI), all-cause mortality, cardiovascular (CV) death, coronary revascularization, major bleeding, and stent thrombosis. Using random-effects models, they pooled hazard ratios (HRs) to compare the two antiplatelet strategies. These results found that clopidogrel monotherapy led to a 31% lower risk of stroke (HR: 0.69; 95% CI: 0.51–0.94; p = 0.02; I² = 28%) compared with aspirin. Similarly, the risk of myocardial infarction was reduced by 29% among clopidogrel users (HR: 0.71; 95% CI: 0.51–0.99; p = 0.05; I² = 48%). There were no significant differences between the 2 drugs in terms of all-cause mortality (HR: 0.99; 95% CI: 0.78–1.25; p = 0.92), cardiovascular death (HR: 0.87; 95% CI: 0.70–1.08; p = 0.22), or need for coronary revascularization (HR: 0.95; 95% CI: 0.83–1.09; p = 0.44). Rates of major bleeding were comparable between both groups (HR: 0.97; 95% CI: 0.70–1.35; p = 0.87), suggesting that clopidogrel’s enhanced efficacy does not come at the cost of increased bleeding risk. Also, stent thrombosis showed no significant difference (HR: 0.66; 95% CI: 0.38–1.15; p = 0.15). The analysis highlights that clopidogrel monotherapy after DAPT not only reduces the risk of stroke and myocardial infarction when compared to aspirin but also maintains a comparable safety profile regarding bleeding and mortality. These results reinforce the upcoming evidence that clopidogrel, long used in combination therapy, may stand on its own as a potent and safe long-term antiplatelet agent. Overall, these findings may influence upcoming clinical guidelines, prompting cardiologists to reconsider whether aspirin should remain the default single antiplatelet therapy post-PCI. Waqas, S. A., Imran, Z., Bilal, A. R., Ahmed, S., Gaba, H., Chew, N. W. S., Greene, S. J., & Khan, M. S. (2025). Efficacy of clopidogrel monotherapy versus aspirin monotherapy after percutaneous coronary intervention. Journal of Thrombosis and Thrombolysis.https://doi.org/10.1007/s11239-025-03185-0