Background: There is paucity and controversy of evidence regarding the optimal duration of dual antiplatelet therapy. Zotarolimus-eluting stents (ZES) have favorable long-term safety profiles, and the duration of dual anti-platelet therapy can be shorter with ZES than with other stents, theoretically. This study aims to determine the feasibility of 6-month dual antiplatelet therapy after ZES implantation in real world practice. Methods and Results: Between March 2006 and January 2010, 2840 patients were enrolled in multicenter registry for 6-month dual antiplatelet therapy (aspirin 100-200mg+clopidogrel 75mg daily) followed by aspirin mono-therapy after ZES implantation. Major exclusion criteria were: cardiogenic shock, previous drug-eluting stent implantation, severe left ventricular dysfunction. The primary outcome was a composite of cardiac death, myocardial infarction (MI), or stent thrombosis (ST) at 1 year. More than half of the patients (61.3%) presented with acute coronary syndrome (ACS). The mean duration of dual antiplatelet therapy was 248짹131 days. At 1 year, 21 patients (0.7%) had cardiac deaths, 34 patients (1.2%) had MI, and 5 patients (0.2%) had definite or probable ST, leading to the primary outcome in 54 patients (1.9%). Death (1.3%), MI, or any revascularization (7.5%) occurred in 273 patients (9.6%). Patients who were event-free at 6 months (n=2717) were divided into 2 groups, according to their duration of clopidogrel use. Patients taking clopidogrel for 6 months were classified as group I (n=1099) and those taking clopidogrel for more than 6 months were classified as group II (n=1618). Group II patients had more severe cardiac risk profiles in baseline (dyslipidemia, ACS, lower left ventricular ejection fraction [LVEF]), angiographic (multi-vessel coronary disease), and procedural characteristics (multi-lesion intervention). The mean duration of dual antiplatelet therapy was 96짹23 days in group I and 354짹37 days in group II (p<0.001). Discontinuation of clopidogrel at 6 months did not increase the primary outcome (Adjusted hazard ratio [HR] 1.91, 95% confidence interval [CI] 0.47-7.77, p=0.47); cardiac death, MI, or target lesion revascularization (Adjusted HR 0.93, 95% CI 0.60-1.44, p=0.76); and death, MI, or any revascularization (Adjusted HR 0.85, 95% CI 0.59-1.21, p=0.37). These results were consistent among various subgroups, i.e. age 65 years, sex, diabetes mellitus, ACS, LVEF 55%, and multi-vessel coronary disease with interaction p values 0.46, 0.92, 0.50, 0.98, 0.50, and 0.63, respectively. Conclusions: Six-month dual anti-platelet therapy followed by aspirin alone seems to be feasible after ZES implantation in real world practice.