Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist is the cornerstone of treatment to prevent recurrent atherothrombotic events in patients with acute coronary syndrome (ACS) and undergoing percutaneous coronary interventions (PCI) (1). Clopidogrel is the most widely used platelet P2Y12 receptor inhibitor. Despite the clinical efficacy of clopidogrel, numerous studies have shown a broad inter-individual variability in the response to this antiplatelet agent (2). Importantly, patients with high (HPR) and low (LPR) platelet reactivity while receiving clopidogrel therapy have an increased risk of recurrent ischemic events, including stent thrombosis and bleeding complications, respectively ((3),4). These findings have set the basis for investigations aimed to define a “therapeutic window” of platelet reactivity that defines a range of P2Y12 receptor-mediated antiplatelet effects associated with a reduced risk of ischemic and bleeding complications (Figure 01_gr1) (5). The broadening of the armamentarium of P2Y12 receptor inhibitors currently available for clinical use, including prasugrel and ticagrelor, have indeed represented an important step forward toward reaching such therapeutic goals (6). These novel generation P2Y12 receptor inhibitors are characterized by potent antiplatelet effects and a greater reduction in atherothrombotic recurrences compared with clopidogrel in ACS patients (6). However, despite these benefits, numerous reasons account for the need or desire to switch a patient from a more potent P2Y12 receptor inhibitor to clopidogrel. These include the higher risk of bleeding, development of side effects, and increased costs of these new agents compared with generic clopidogrel. However, to date studies have mostly focused on the effects of switching from clopidogrel to a novel generation P2Y12 receptor inhibitor, and despite being broadly performed in clinical practice, there is a paucity of information on switching from one of the novel generation P2Y12 receptor inhibitors to clopidogrel (7).