Purpose of Review <p>This review evaluates the comparative efficacy, safety, and clinical applicability of aspirin versus clopidogrel for long-term secondary prevention of coronary artery disease (CAD). It evaluates the use of clopidogrel as long-term monotherapy in stable CAD after dual antiplatelet therapy, with consideration of bleeding risk, tolerability, pharmacogenomics, and guideline recommendations.</p> Recent Findings <p>Recent randomized controlled studies, extended follow-up analyses, and large-scale meta-analyses consistently show that clopidogrel monotherapy provides at least comparable, and in several reports superior protection against major adverse cardiovascular and cerebrovascular events compared with aspirin. These benefits are achieved without an increase in major bleeding and, in certain populations, with a lower bleeding risk. Evidence from contemporary post–percutaneous coronary intervention cohorts further demonstrate a more favorable net clinical benefit with clopidogrel, particularly among patients with heightened susceptibility to bleeding.</p> Summary <p>Both aspirin and clopidogrel remain effective options for long-term secondary prevention in CAD. However, accumulating evidence supports a more individualized approach to antiplatelet selection. Clopidogrel may be preferred in selected patients, particularly after PCI or in those with heightened bleeding risk or aspirin intolerance. Further prospective, head-to-head randomized trials are needed to definitively inform optimal long-term antiplatelet strategies.</p>