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Background and purpose Endovascular treatment (EVT) is superior to medical management (MM) for patients with acute large infarcts. However, evidence remains limited for patients with large infarcts with extracranial internal carotid artery occlusion (e-ICAO) . This study compares EVT and MM in patients with large infarcts due to e-ICAO.Methods Patients with e-ICAO were selected from the ANGEL-ASPECT randomized controlled trial conducted at 46 stroke centers across China between October 2, 2020 and May 18, 2022. The efficacy and safety of EVT and MM were compared in these patients. The primary outcome was the 90-day modified Rankin Scale (mRS) score, and secondary outcomes were 90-day/1-year functional independence and independent ambulation and 1-year mRS score. Safety endpoints were symptomatic intracranial hemorrhage (sICH) and 90-day mortality.Results Of 456 enrolled patients, 76 (16.7%) had e-ICAO (41 EVT, 35 MM). 90-day mRS distribution (4 (2–6) vs 4 (3–5), adjusted common OR (acOR) 1.27 (95% CI 0.54 to 2.98); P=0.579), 90-day independent ambulation (46.3% vs 31.4%, aRR 1.29 (95% CI 0.70 to 2.38); P=0.415), 90-day functional independence (29.3% vs 5.7%, aRR 3.74 (95% CI 0.89 to 15.61); P=0.071), 1-year mRS score (4 (2–6) vs 4 (3–5), acOR 0.86 (95% CI 0.35 to 2.10), P=0.735), 1-year independent ambulation (48.7% vs 46.9%, aRR 0.79 (95% CI 0.48 to 1.31); P=0.367), and 1-year functional independence (30.8% vs 15.6%, aRR 1.76 (95% CI 0.67 to 4.65); P=0.252) were not significantly different between the EVT and MM groups. sICH was higher in the EVT group than in the MM group (2.4% vs 0, P=0.356) and 90-day mortality (19.5% vs.8.6%, aHR 2.17 (95%CI 0.59 to 8.03); P=0.247) was similar between the two groups.Conclusions In patients with large infarcts and e-ICAO, EVT did not improve clinical outcomes at either 90 days or 1 year compared with MM without increasing the risk of sICH and mortality.Trial registration number NCT04551664.