AIMS: Peripheral artery disease (PAD) is associated with increased risk of cardiovascular events. The benefits of dual antiplatelet therapy (DAPT) vs single antiplatelet therapy (SAPT) with aspirin in patients with PAD remain subject of ongoing debate. METHODS AND RESULTS: We performed a meta-analysis of studies comparing DAPT vs aspirin monotherapy in PAD. Incidence rate ratios (RR) and respective 95% confidence intervals (CI) were used as summary statistics. The primary outcome was mortality. Secondary endpoints were ischemic and bleeding outcomes. Ten studies including 65,675 patients have been included. Compared to SAPT, DAPT was associated with a significant reduction in mortality: RR, 0.89; 95% CI, 0.86-0.92; P < 0.001. Results were consistent across patients with symptomatic PAD and those undergoing bypass or percutaneous transluminal angioplasty (PTA). Similarly, DAPT significantly reduced the risk of repeat peripheral revascularizations (RR, 0.80; 95% CI, 0.69-0.92; P = 0.002). No significant increase of major bleeding complications was observed with DAPT as compared to SAPT (RR, 1.21; 95% CI, 0.87-1.68 P = 0.26). CONCLUSIONS: DAPT, as compared to SAPT, significantly reduces mortality in patients with PAD, with no significant increase in bleeding complications. These findings support DAPT as the mainstay antiplatelet therapeutic regimen in patients with PAD.