AIMS:Dual antiplatelet treatment (DAPT) is a cornerstone in the treatment of acute coronary syndrome (ACS) but the optimal treatment duration is unclear. We aimed to evaluate the effect of DAPT duration with clopidogrel and aspirin on the recurrence of ischaemic events and bleeding in a large, unselected ACS population. METHODS AND RESULTS:We performed a prospective, observational cohort study of patients in Sweden (n = 56 440) admitted for ACS, with prescribed DAPT and hospitalized between January 2006 and July 2010. Patients were obtained from the SWEDEHEART register and data were merged with registers from the National Board of Health and Welfare. Depending on dispensed clopidogrel tablets, patients were divided into groups based on DAPT duration with clopidogrel and aspirin (3 months: 84-100 clopidogrel tablets (t); >3 months: >100 t; 6 months: 168-200 t; >6 months: >200 t). For the combined primary endpoint, defined as all-cause death, stroke, or re-infarction, only patients with an uneventful first 3-month period (no death, stroke, re-infarction, bleeding, stent thrombosis, or revascularization) were included. The incidence of the primary endpoint was 45 events per 1000 person-years in the >3 months DAPT group compared with 65 events per 1000 person-years in the 3 months DAPT group [adjusted HR 0.84, 95% CI (0.75; 0.95)]. Bleeding was more common in the >3 months treatment group (adjusted HR 1.56, 95% CI (1.18; 2.07), but the number of events was small. For >6 vs. 6 months DAPT, the adjusted HR for the combined endpoint was 0.75 with 95% CI (0.59; 0.95). CONCLUSION:In this contemporary, large real-life ACS population, DAPT for more than 3 months compared with a shorter duration was associated with a lower risk of death, stroke, or re-infarction. TRIAL REGISTRATION:Clinicaltrials.gov (NCT01623700).