Abstract Background Atrial fibrillation (AF) patients receiving haemodialysis (HD) face increased bleeding risks, so the net benefit of stroke prophylaxis by oral anticoagulation (OAC) is ill defined. Left atrial appendage closure (LAAC) might serve as a suitable alternative to OAC for stroke prevention in this high-risk cohort. Objective To determine the safety and clinical efficacy of LAAC in HD patients with AF. Methods In an international multi-center (n=9) registry, the clinical details were compiled from all HD+AF patients who underwent LAAC. Results The cohort included 147 patients: age 72.6 ± 10.4 yrs, 73% male, CHA2DS2-VASc 4.5 ± 1.5, HAS-BLED 4.7 ± 1.2, prior stroke/TIA 22,5%, prior major bleed 57,8%. The pre-LAAC anticoagulation regimen was heterogeneous with a wide array of at least 12 different combinations of medications utilized. A total of 149 procedures were performed and LAAC was successful in 98% (146 of 149), with a median procedure time of 43 (30-66) minutes. The most common device was Watchman (61%), followed by Amulet (23,3%). The rate of major complications was 5,4% (8), same as the rate of minor complications (5,4%), leading to an overall complication rate of 10,7% (16/149) including one fatal bleed the day after implantation, 4 (2.7%) cardiac tamponades of which 3 were treated with pericardiocentesis and one surgery, and 2 device dislodgements requiring percutaneous retrieval followed by successful reimplantation. Most patients were discharged on DAPT (61,6%). At a median of 61 days follow-up, imaging was performed in 83% of patients, revealing: only 2 (1.7%) peri-device leaks ≥5 mm, and no DRT. Subsequently, anticoagulation was shifted to SAPT so that SAPT emerged as the predominant anticoagulation regimen representing 165,9 patient years (py) of usage followed by DAPT (41,8 py). Over the follow-up of 222,9 py, the incidence of ischemic stroke was 0,9% per year (2 strokes in total), reflecting an 88% relative risk reduction (p<0,001) compared with the calculated stroke rate of 7,4% for patients with a similar CHA2DS2VASc score and no anticoagulation. Similarly, the rate of major bleeding events (defined as BARC score ≥3) was 4,5% per year, signifying a 55% relative risk reduction (p=0,023) compared to the expected rate of patients on VKA therapy, based on a comparable HAS-BLED score. Event tough time on SAPT was nearly four times longer than on DAPT, the number of major bleeding events was similar (SAPT: 5; DAPT: 4). Conclusion In light of these findings LAAO emerges as a promising solution for this unique patient cohort. By mitigating the risks of both bleeding complications associated with anticoagulation and the threat of stroke in the absence of anticoagulation, LAAO represents a well-balanced and effective therapeutic strategy for these individuals. However, the procedural complication rate was elevated compared to that observed in other LAAC cohorts, and requires further study.