Primary percutaneous coronary intervention (PPCI) is superior to thrombolysis in STEMI (ST segment elevation myocardial infarction) patients. Data on late stent thrombosis (ST) have raised concerns regarding the use of drug-eluting stents during PPCI. We report the first 3-year clinical evaluation of the zotarolimus-eluting stent (ZES) in patients undergoing PPCI for STEMI, a single-center, prospective cohort study of consecutive patients admitted with STEMI. All underwent PPCI within 12 hours of symptoms; each received one or more ZES in one or more target lesions. All patients received aspirin 300 mg, clopidogrel 600 mg, abciximab, and unfractionated heparin. A total of 102 STEMI patients (76 male, mean 62 years) received 162 ZES (mean 1.6 stents/patient). Median call-to-balloon time was 123 (102–152) minutes. Thirty-day combined major adverse cardiovascular event (MACE) rate was 3.9% (n = 4). Subacute ST occurred in 2 patients (1.96%). Combined MACE rates at 12 months and 3 years were 7.8% (n = 8) and 13.7% (n = 14). Late ST occurred in 1 patient (1%) with no occurrence of very late ST. This is the first 3-year report of the use of the ZES in an unselected, consecutive PPCI population. Overall 3-year incidence of MACE and target lesion revascularization (5.9%) was low, and was comparable to that seen with sirolimus- and paclitaxel-eluting stents in randomized controlled trials. At 3 years there was no occurrence of very late ST.