Dual antiplatelet therapy (DAPT) is recommended for 6–12 months after drug-eluting stent (DES) implantation to prevent ischemic events and late stent thrombosis. The optimal duration of DAPT has not been established. We performed a meta-analysis of the comparative effects of short and long versus standard duration DAPT duration on adverse cardiovascular and major bleeding. We conducted an EMBASE and MEDLINE search for studies in which patients were randomized to treatment with a different duration of DAPT. We included studies that provided data on DES selection, DAPT regimen and duration, and incidence of the selected endpoints at the end of the follow-up period. We identified 5 prospective randomized studies comparing short versus standard duration DAPT and 3 comparing long versus standard duration DAPT with a total of 28,343 patients. Short-term DAPT has similar incidence of stent thrombosis, MI, and death compared to standard duration DAPT, whereas major bleeding was significantly lower in short duration DAPT. Long-term DAPT was associated with lower rates of stent thrombosis and MI but significantly increased major bleeding and all-cause mortality compared to standard duration DAPT. In this meta-analysis of prospective controlled studies we found that short duration DAPT is safer and as effective as standard duration DAPT in patients with second-generation DES. Extended DAPT is associated with less ischemic events at the expense of high bleeding and mortality rates.