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Background and Objectives: Although previous trials have established the efficacy and safety of endovascular thrombectomy (EVT) in large ischemic core strokes, most of them excluded patients with extracranial internal carotid artery (e-ICA) occlusion. We aimed to compare outcomes in patients with e-ICA occlusion and large ischemic core infarcts treated with EVT vs medical management (MM)., Methods: This was a secondary analysis of the SELECT2 trial, a randomized controlled trial conducted at 31 international sites. Adult patients with proximal intracranial anterior circulation large ischemic strokes, defined as Alberta Stroke Program Early CT Score (ASPECTS) 3-5 on noncontrast CT or ischemic core ≥50 mL on CT-perfusion/magnetic resonance-diffusion imaging, and concomitant e-ICA occlusion were selected. The primary outcomes were the distribution of modified Rankin Scale (mRS) score at 90-day follow-up and symptomatic intracranial hemorrhage (sICH)., Results: Among 352 enrolled patients, 62 (17.6%) with e-ICA occlusions were included. Of those 62 patients, 37 received EVT (median [interquartile range (IQR)] age, 65 [58-71] years; 15 women [38.5%]) and 25 received MM (median [IQR] age, 66 [61-71] years; 7 women [28%]). ASPECTS (EVT: 5 [3-5] vs MM: 5 [4-5]) and ischemic core volume (EVT: 100 [69-134] mL vs MM: 103 [78-135] mL) were similar between groups. The successful reperfusion rate with EVT was 64.9%. Patients receiving EVT demonstrated significantly better functional outcomes (adjusted generalized odds ratio 2.51; 95% CI 1.43-4.39; p = 0.001) and a higher proportion of patients achieving 90-day independent ambulation (EVT: 37.8% vs MM: 8%; adjusted relative ratio [aRR] 4.58; 95% CI 1.18-17.79; p = 0.037) and functional independence (EVT: 21.6% vs MM: 8%; aRR 2.16; 95% CI 0.53-8.83; p = 0.285). Furthermore, no heterogeneity of EVT benefit was observed by the presence or absence of e-ICA occlusion ( p -interaction = 0.248). There were no sICH or parenchymal hemorrhage type 2 events in either group, and mortality was similar in the 2 groups (aRR 0.75; 95% CI 0.39-1.45; p = 0.388)., Discussion: Among patients with e-ICA occlusions and large ischemic core stroke, EVT was associated with better functional outcomes without significant safety concerns when compared with MM. Our findings suggest that EVT in these patients is beneficial, while the optimal treatment of the extracranial carotid occlusion remains unclear., Trial Registration Information: Name of the trial: SELECT2 trial. Registration number: ClinicalTrials.gov Identifier: NCT03876457. Date of registration submission: August 3, 2019. Date of first patient enrollment: November 10, 2019., Classification of Evidence: This study provides Class II evidence that for patients with large core acute ischemic stroke and concomitant e-ICA occlusion, EVT is associated with better functional outcome at 90 days compared with MM alone.