INTRODUCTION Several high quality randomized controlled studies were recently published on non-vitamin K oral anticoagulants (NOACs) in patients with or at risk for coronary artery (CAD) or peripheral artery disease (PAD). While a reduction on cardiovascular event is known and an increase in moderate bleeding is expected, the effect of this strategy on survival is currently unknown. Accordingly, we performed a comprehensive systematic review and meta-analysis of randomized controlled trials to investigate the effect of NOAC on survival. EVIDENCE ACQUISITION We searched Pubmed, EM-BASE, Cochrane Central Register, and Clinicaltrials.gov (last updated March 31st 2019). The primary endpoint was all-cause mortality at the longest reported follow-up. Coprimary endpoint was major bleeding according to the International Society on Thrombosis and Hemostasis (ISTH) criterion. EVIDENCE SYNTHESIS We included ten randomized controlled trials comparing NOACs versus control treatment (placebo, single platelet or dual antiplatelet therapy) enrolling 66665 patients with or at risk for CAD or PAD. NOACs were associated with a decreased risk of mortality (825/41655 [4.4%] versus 405/25010 [5.6%] RR 0.93 [95% CI: 0.87-1.00], P=0.04), and an increased risk for major bleeding (RR 1.62 [95% CI: 1.23-2.13], P=0.0005) when compared to control. Findings were robust to trial sequential, subgroup, and sensitivity analyses. Low doses NOACs were associated with a reduced mortality when compared to standard dose NOACs. CONCLUSIONS NOACs reduced all-cause mortality in patients with or at risk for CAD or PAD, even though they increased the risk of major bleeding. Future studies regarding the best doses of NOACs are warranted.