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The optimal duration of dual antiplatelet therapy (DAPT) in patients with ischaemic cardiovascular (CV) disease is still debated. Previous meta-analyses reported conflicting results about prolonged DAPT on mortality and major CV events. Aim of this study was to assess the effects of prolonged vs. no/short-term DAPT on myocardial infarction (MI), stroke, bleeding, and mortality.Trial inclusion criteria were: randomization to prolonged duration vs. no/short DAPT; reporting of at least one outcome among overall and CV death, MI, stroke, major non-fatal, fatal, and intracranial bleeding. Fifteen randomized studies including 85 265 patients were included. Prolonged DAPT, compared with no or short DAPT, significantly reduced MI (RR: 0.785, 95% CI: 0.729–0.845, P < 0.001) and stroke (RR: 0.851, 95% CI: 0.754–0.959, P = 0.008), but had no effect on overall (RR: 0.989, 95% CI: 0.921–1.061, P = 0.751) or CV (RR: 0.951, 95% CI: 0.872–1.037, P = 0.258) mortality. Prolonged DAPT significantly increased major non-fatal (RR: 1.690, CI: 1.322–2.159, P < 0.001), but not intracranial or fatal bleeding (RR: 1.236, CI: 0.899–1.698, P = 0.192, RR: 1.069, CI: 0.760–1.503, P = 0.703; respectively). The effects of DAPT were similar to those reported in the overall analysis in patients with stable CV disease, whereas in those with unstable CV disease only the significant reduction of stroke was not confirmed. Dual antiplatelet therapy prolonged beyond 1 year significantly reduced MI but not stroke, all-cause, or CV death. It significantly increased the risk of major non-fatal bleeding, with no difference in intracranial and fatal bleeding.Prolonged DAPT significantly reduced ischaemic CV events but not mortality. Even if a significant increase of major non-fatal bleeding was detected, no increased risks of intracranial and fatal bleeding were observed.