Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in adults and it is related to morbidity like ischemic stroke (IS) that is reduced from anticoagulation therapy. Nowadays direct oral anticoagulants (DOAC) are reccomended as a first choice (excluding patients with mechanical heart valve and moderate to severe mitral stenosis) regardless of age. However only one third of patients aged over 75 years were enrolled in the randomized trials and few data of real world are available. Methods We retrospectively included all patients aged > 75 years who received edoxaban for IS prevention in AF between january 2016 to december 2023 under an authorized therapeutic plan. We evaluated demographic features , efficacy and safety considering patients older than 75 years and those older than 85 years .We also analyzed prescriptive appropriateness. Results Out of 1576 with average age 83 years old ( 79 – 87 ), average weight 70 kg ( 60 – 78 ) and average CHA2DS2VAsc 4 ( 4-5), 56 % were females, 89 % suffered from arterial hypertension,18% diabetes mellitus,18% heart failure,36% cognitive impairment,13 % previous stroke, 22% previous cancer . After 36 months ( 12 – 60) of follow up , efficacy endpoint ( Stroke, TIA and systemic embolism) was 4,3% without sex difference [ males no endpoint (NE) 45% vs endpoint (E) 41% and females ( NE) 59% vs ( E) 55% ; p= 0,5) and without age difference [ > 75 years (E) 65% vs ( NE) 59%and ≥85 years (E) 35% vs (NE) 41%; p = 0,3). Major bleeding (MB) were 7,8% without sex difference [males no bleeding ( NoB) 45 % vs bleeding (B) 48% and females (NoB) 55 % vs (B) 52% ; p=0,5 ) but with prevalent MB in > 85 years patients [≥85 years: (B)53% vs (NB) 40% vs <85 years (B) 47% vs (NB) 60%; p = 0,003). Prescriptive appropriateness was registered in 89% patients at initial evaluation and 90% at last follow up . Conclusions Our study confirms efficacy and safety of edoxaban for IS prevention in AF also in elderly and in very elderly. However a higher incidence of MB was observed in very elderly reletive to the elderly and this finding increased with longer treatment duration. These data highlight the need for more intensive clinical ed laboratory followu in very eldery receiving this therapy.