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Introduction: The role of anticoagulation in octogenarians and nonagenarians with atrial fibrillation (AF) is controversial due to the lack of evidence from randomized controlled trials (RCTs), owing to the under representation of these patients in clinical trials. Aim: In the present meta-analysis we aim at comparing the clinical benefits and risk of anticoagulation (AC) with no AC in octogenarians and nonagenarians. Methods: We systematically searched MEDLINE/PubMed, EMBASE/Ovid, and Web of Science databases from the inception to October, 2020. Studies were eligible for inclusion if they met the following criteria: studies comparing AC with no AC in patients aged 80 or more for AF and reported thromboembolic events (TE) and bleeding outcomes. We used Mantel-Haenszel method with a Paule-Mandel estimator of Tau2 with Hartung Knapp-Sidik-Jonkman adjustment to estimate risk ratio (RR) with a 95% confidence interval (CI). Outlier analysis was used to adjust for statistical heterogeneity. Results: A total of 10 observation studies and 1 RCT were included in the final analysis. There was no difference in the risk of TE with AC in octogenarians and nonagenarians compared with no AC, before [RR: 0.87, 95% CI 0.62–1.23, I2: 71%, GRADE confidence "very low"] and after [RR: 0.83, 95% CI 0.66–1.04, I2: 55.5%] adjusting for statistical heterogeneity among studies. In the unadjusted analysis, no difference in the risk of bleeding events was observed between both groups [RR: 1.05, 95% CI 0.62–1.77, I2: 86%, GRADE confidence "very low"]. After adjusting for heterogeneity, AC was associated with an increased risk of bleeding compared with those not receiving AC [RR: 1.57, 95% CI 1.44–1.71, I2: 0%]. AC in octogenarians was not associated with a net clinical benefit compared with no AC. Conclusions: This meta-analysis did not demonstrate any difference in the risk TE in octogenarians and nonagenarians with AF on AC vs. no AC, in both the adjusted and unadjusted analyses. Also, the risk of bleeding events in the unadjusted analysis was similar between both groups. The adjusted analysis showed an increased risk of bleeding in the AC group compared with no AC group. More data is needed to establish safety and efficacy of AC in this vulnerable patient population. The results of this analysis should be interpreted with caution due to the observational nature of most studies included, and the only RCT reported lower rates of TE and similar risk of bleeding. [ABSTRACT FROM AUTHOR]