BACKGROUND: The optimal duration of dual antiplatelet therapy (DAPT) after drug-eluting stent (DES) implantation is unclear, and its risks and benefits may vary according to DES generation. OBJECTIVES: The goal of this study was to evaluate the efficacy and safety of DAPT after DES implantation. METHODS: We included randomized controlled trials that tested different durations of DAPT after DES implantation: shorter dual antiplatelet therapy (S-DAPT) was defined as the per-protocol minimum duration of DAPT after the procedure, and longer dual antiplatelet therapy (L-DAPT) was defined as the per-protocol period of more prolonged DAPT. The primary efficacy and safety outcomes were definite/probable stent thrombosis and clinically significant bleeding (CSB), respectively. RESULTS: Ten randomized controlled trials (N = 32,135) were included. Compared with L-DAPT, S-DAPT had an overall higher rate of stent thrombosis (odds ratio [OR]: 1.71 [95% confidence interval (CI): 1.26 to 2.32]; p = 0.001). The effect of S-DAPT on stent thrombosis was attenuated with the use of second-generation DES (OR: 1.54 [95% CI: 0.96 to 2.47]) compared with the use of first-generation DES (OR: 3.94 [95% CI: 2.20 to 7.05]; p for interaction = 0.008). S-DAPT had an overall significantly lower risk of CSB (OR: 0.63 [95% CI: 0.52 to 0.75]; p < 0.001). Finally, a numerically lower all-cause mortality rate was observed with S-DAPT (OR: 0.87 [95% CI: 0.74 to 1.01]; p = 0.073). CONCLUSIONS: S-DAPT had overall lower rates of bleeding yet higher rates of stent thrombosis compared with L-DAPT; the latter effect was significantly attenuated with the use of second-generation DES, although the analysis may have been limited by the varying DAPT durations among studies. All-cause mortality was numerically higher with L-DAPT without reaching statistical significance. Prolonging DAPT requires careful assessment of the trade-off between ischemic and bleeding complications.