The optimal duration of dual antiplatelet therapy (DAPT) after implantation of newer-generation drug-eluting stents (DES) remains uncertain. Similarly, questions remain about the role of DAPT in long-term therapy of stable post-myocardial infarction (MI) patients. Our objective was to compare the incidence of death, major hemorrhage, MI, stent thrombosis, and major adverse cardiac events in patients randomized to prolonged or short-course DAPT after implantation of newer-generation DES and in secondary prevention after MI. We used traditional frequentist statistical and Bayesian approaches to address the following questions: Q1) What is the minimum duration of DAPT required after DES implantation? Q2) What is the clinical benefit of prolonging DAPT up to 18 to 48 months? Q3) What is the clinical effect of DAPT in stable patients who are >1 year past an MI? We reviewed evidence from 11 randomized controlled trials (RCTs) that enrolled 33 051 patients who received predominantly newer-generation DES to answer: A1) Use of DAPT for 12 months, as compared with use for 3 to 6 months, resulted in no significant differences in incidence of death (odds ratio OR: 1.17; 95% confidence interval CI: 0.85 to 1.63), major hemorrhage (OR: 1.65; 95% CI: 0.97 to 2.82), MI (OR: 0.87; 95% CI: 0.65 to 1.18), or stent thrombosis (OR: 0.87; 95% CI: 0.49 to 1.55). Bayesian models confirmed the primary analysis. A2) Use of DAPT for 18 to 48 months, compared with use for 6 to 12 months, was associated with no difference in incidence of all-cause death (OR: 1.14; 95% CI: 0.92 to 1.42) but was associated with increased major hemorrhage (OR: 1.58; 95% CI: 1.20 to 2.09), decreased MI (OR: 0.67; 95% CI: 0.47 to 0.95), and decreased stent thrombosis (OR: 0.45; 95% CI: 0.24 to 0.74). A risk-benefit analysis found 3 fewer stent thromboses (95% CI: 2 to 5) and 6 fewer MIs (95% CI: 2 to 11) but 5 more major bleeds (95% CI: 3 to 9) per 1000 patients treated with prolonged DAPT per year. Post hoc analyses provided weak evidence of increased mortality with prolonged DAPT. We reviewed evidence from 1 RCT of 21 162 patients and a post hoc analysis of 1 RCT of 15 603 patients to answer: A3): Use of DAPT >1 year after MI reduced the composite risk of cardiovascular death, MI, or stroke (hazard ratio: 0.84; 95% CI: 0.74 to 0.95) but increased major bleeding (hazard ratio: 2.32; 95% CI: 1.68 to 3.21). A meta-analysis and a post hoc analysis of an RCT in patients with stable cardiovascular disease produced similar findings. The primary analysis provides moderately strong evidence that prolonged DAPT after implantation of newer-generation DES entails a tradeoff between reductions in stent thrombosis and MI and increases in major hemorrhage. Secondary analyses provide weak evidence of increased mortality with prolonged DAPT after DES implantation. In patients whose coronary thrombotic risk was defined by a prior MI rather than by DES implantation, the primary analysis provides moderately strong evidence of reduced cardiovascular events at the expense of increased bleeding.