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Background: Currently, endovascular treatment is advocated for middle cerebral artery (MCA) occlusions, however not much is known about the natural history of an M1 compared to an M2 occlusion.Objective: To compare the clinical outcome in endovascularly treated patients with proximal vessel occlusion (M1) versus a more distal occlusion (M2) among patients with ischemic stokes in a negative trial.Methods: Data from Interventional Management of Stroke trial (IMS-III) for patients with acute ischemic stroke with distal MCA (mainly M2 and beyond) occlusions diagnosed by either computed tomographic angiography (CTA) or catheter angiography were analyzed. NIHSS at admission, baseline characteristics, infarct volume at baseline and outcome at 90 days (mRS score) were compared between the two groups. Favorable outcome was defined by discharge modified Rankin scale (mRS) score of 0-2, at 3 months. Multivariate logistical regression was performed to compare the outcomes after adjusting for potential confounders.Results: Of the 434 from the endovascular therapy group, 215 (49.5%) and 98 (22.5%) patients had M1 and M2 occlusion respectively. Patients with M1 occlusion had higher mean NIHSS at admission (18.76± 4.94 versus 17.37± 5.72, P-value = 0.029) and higher infarct volume (105.92 ± 113.23versus 49.67 ± 63.42, P-value = 0.000). Rate of favorable outcome defined by mRS at discharge was lower among patients with M1 (31.53%vs.46.67%p-value = 0.0128). After adjusting for age, sex, total NIHSS score at admission, hepato-biliary disorders, anticoagulants, antiplatelet, NSAIDS, patients with M1 occlusion had higher rates of poor outcomes; odds ratio (OR) 1.819 (confidence interval [CI] 1.032- 3.205, P=0.03860).Conclusions: In patients enrolled in IMS-III trial, an M1 occlusion demonstrated a larger tissue infarct size and a lower rate of favorable outcome than an M2 occlusion, given the negative results of the trial, these findings reflect the natural history of these two occlusion sites.