A 54-year-old male with multiple cardiovascular risk factors and past medical history of long-standing dyspnea was admitted for acute respiratory failure. Physical examination revealed near-normal blood pressure, sinus tachycardia, tachypnea, and reduced oxygen saturation (90%) with mild distal-limb cyanosis. On admission ECG, chest X-ray, transthoracic echocardiography, and laboratory tests were performed to exclude new-onset heart failure and/or an acute coronary syndrome. Then, he underwent pulmonary CT angiography seeking for pulmonary embolism that showed a voluminous pulmonary arterio-venous malformation (PAVM) with the feeding artery coming from the right pulmonary artery and venous drainage confluent into the right pulmonary vein (Panel 1A and C). A thrombophilic screening showed a heterozygous mutation for the methylenetetrahydrofolate reductase-1 gene and reduced serum-free protein S levels. The invasive left–right heart catheterization revealed mild-to-moderate pulmonary hypertension and moderate arterial desaturation (O2 saturation, 91%). Considering the large size of both the feeding artery and vein drainage (10 mm) and in order to reduce postprocedural embolization risk and recanalization rate,1,2 a contemporary percutaneous embolization of both PAVM branches (Panel 1C and D; Supplementary material online, Videos S1–3) with two Amplatzer Vascular Plug (AVP) II® 20 mm (Abbott, Plymouth, MN, USA) was planned using a double access technique, transfemoral trans-septal (retrograde) and transfemoral transpulmonary (anterograde) with a post-procedural improvement of arterial saturation (up to 99%). The patient was discharged with a marked clinical improvement (NYHA Class I) and complete exclusion of the PAVM at six months follow-up (Panel 1E and F).