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Background: The benefit of endovascular treatment in acute ischemic stroke patients with occlusion of distal middle cerebral artery (M2 segment) is unclear.Methods: We analyzed data from subjects with occlusion of M2 segment of middle cerebral artery confirmed with computed tomographic (CT) angiogram who were randomized to either intravenous (IV) recombinant tissue plasminogen activator (rt-PA) alone or in combination with endovascular treatment. We compared the rates of neurological deterioration within 24 hours; symptomatic intracranial hemorrhage (ICH) within 30 hours; good quality of life (defined by EQ-5D index score of ≥0.6) and functional independence (defined by modified Rankin scale of 0-2) at 3 months among subjects who underwent endovascular treatment with subjects who received IV rt-PA alone.Results: Of these 51 subjects (mean age ±SD; 68.3±11.8 years) with M2 segment occlusion, 34 and 17 subjects received IV rt-PA followed by endovascular treatment and IV rt-PA alone, respectively. There was a non-significantly lower rate of neurological deterioration (14.7% versus 25.0%) and symptomatic intracranial hemorrhages (5.9% versus 17.6%) among subjects who received IV rt-PA followed by endovascular treatment. At 3 months, the rates of independent functional outcome (52.9% versus 41.2%, odds ratio [OR] 1.6; 95 % confidence interval [CI] 0.5-5.2; P = 0.46) and good quality of life (50.0% vs 35.3% OR 1.9; 95% CI 0.5-7.2; p=0.37) were non-significantly higher among subjects with M2 segment occlusion who received IV rt-PA followed by endovascular treatment. The rate of death within 3 months was significantly lower among those who received IV rt-PA followed by endovascular treatment (5.9% vs 35.3%; OR 0.2; 95% CI 0.1-0.9; p=0.048).Conclusions: A randomized clinical trial should be considered based on the significant reduction in mortality and non-significant increase in functional independence and good quality of life following endovascular treatment in among acute ischemic stroke patients with M2 segment occlusion.