Background: Despite the marked efficacy demonstrated by drug-eluting stents (DES) in reducing neointimal proliferation, and therefore, the need for target lesion revascularization (TLR), persistent concerns regarding long-term safety and efficacy, especially in more complex subset, are still. Methods: The DESIRE Registry is a large, prospective, non-randomized, single center study assessing the late outcomes of unselected pts treated with DES. Overall, 5,541 pts were consecutively enrolled from May/02-Jun/14. Clinical follow-up (FU) (97%) was performed yearly up to 12 yrs (median 4.9 yrs). Stent thrombosis (ST) was defined according to the ARC. Results: Mean age was 65 yrs, 31% had diabetes, 29% current smokers, 42% presented with ACS (17% recent myocardial infarction, MI), and the majority of lesions were highly complex (67% type B2/C). Overall, there were 8,919 lesions treated with 9,537 DES, and angiographic success was 99%. During the FU period, cumulative event rates were major adverse cardiac events (cardiac death, myocardial infarction, or TLR) 32%, myocardial infarction 8%, TLR 21%, and cardiac death 6%. As for stent thrombosis, overal rate was 2.4%, given that 95% of patients were free from this event up to 12 years. In the multivariate model, independent predictors of major adverse cardiac events were: prior revascularization by percutaneous intervention (HR 1.21, p=0.03) or surgery (HR 1.53, p<0.001), dyslipidemia (HR 1.20, p=0.03), renal insufficiency (HR 1.41, p<0.001), peripheral vascular disease (HR 2.06, p<0.001), long lesions (HR 1.38, p<0.001), acute coronary syndrome (HR 1.39, p<0.001), and residual stenosis (HR 1.02, p<0.001). As for stent thrombosis, predictors were: recent myocardial infarction (HR 2.66, p=0.001), multiple stents implanted (HR 1.89, p=0.002), saphenous vein graft (HR 2.21, p=0.004), and residual stenosis (HR 1.03, p=0.03). Conclusions: At very long-term follow-up (up to 12 years) in a large cohort of patients from the real world practice, cumulative event rates included TLR in 21% and stent thrombosis in 2.4%. Overall, there were no safety concers, given that 95% of patients were free from stent thrombosis up to 12 years.