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Atrial fibrillation is the most common cardiac arrhythmia worldwide and represents a major risk factor for cerebral embolic stroke. The standard therapy in the prevention of stroke is oral anticoagulation therapy. However, a considerable number of patients are unable to support chronic OAC. Among these are patients with hereditary hemorrhagic telangiectasia. We present a case of a female patient affected by Rendu-Osler- Weber disease who developed permanent atrial fibrillation with a CHA2DS2-VASc risk score of three. OAC was indicated despite her high bleeding risk. Therefore, an increase of muco-cutaneous and nose bleedings (BARC 2) with several admissions to the Emergency Department and multiple cauterizations influenced a worsening of her quality of life. On that basis OAC was discontinued. After a multidisciplinary evaluation, we decided to perform percutaneous intervention of left atrial appendage closure with implantation of Watchman device. As anti-platelet post procedural therapy, considering her high bleeding risk, we adopted single anti-thrombotic strategy with clopidogrel 75 mg/die, discontinued after three weeks due to increasing in recurrent nosebleeds, needed another cauterization. After 12 month follow up, the patient is in good health, with rare episodes of minor bleedings and a successful and well positioning of the intra-cardiac device, without thrombotic apposition, was evidenced at following echocardiographic examinations. In conclusion percutaneous intervention of LAA closure is confirmed to be an alternative and successful strategy in high bleeding risk patient with a contraindication to OAC. By thorough assessment, a single anti-thrombotic therapy with clopidogrel 75 mg/die, after device implantation and for a time-limited