In patients with coronary artery disease (CAD), aspirin has long represented the cornerstone of antiplatelet therapy for secondary prevention. In patients with an acute coronary syndrome (ACS) and undergoing percutaneous coronary intervention (PCI), oral P2Y12 inhibitors have traditionally been used as adjuncts to aspirin, a strategy known as dual antiplatelet therapy (DAPT). Although DAPT reduces the risk of ischemic recurrences, it carries a risk of bleeding. In CAD patients with a concomitant indication for oral anticoagulation (OAC)-who account for approximately 15% of patients--the combination of aspirin and OAC is associated with an increased risk of bleeding without ischemic benefit. The adverse impact of bleeding on prognosis has prompted investigations aimed at identifying antithrombotic treatment regimens associated with reduced bleeding without compromised ischemic protection. Among these, a strategy of aspirin withdrawal after a brief period of combination therapy has emerged as an attractive option. The efficacy and safety of aspirin withdrawal, however, vary substantially according to clinical setting, patient profile (eg, age, sex, ethnicity, genetic background, and comorbidities), timing of discontinuation after ACS or PCI, and alternative adjunctive antithrombotic therapy, including use of OAC and choice of P2Y12 inhibitor. After reviewing the pharmacologic rationale for aspirin withdrawal, the clinical trial evidence, and guideline recommendations, we provide practical considerations for the implementation of this strategy in patients with CAD, with and without an indication to be on OAC.