Background and Purpose: The best anesthetic management for mechanical thrombectomy of large vessel occlusion strokes is still uncertain and could impact the quality of reperfusion and clinical outcome. We aimed to compare the efficacy and safety outcomes between local anesthesia (LA) and conscious sedation in a large cohort of acute ischemic stroke patients with anterior circulation large vessel occlusion strokes treated with mechanical thrombectomy in current, everyday clinical practice. Methods: Patients undergoing mechanical thrombectomy for anterior large vessel occlusion strokes at 4 comprehensive stroke centers in France between January 1, 2018, and December 31, 2018, were pooled from the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France. Intention-to-treat and per-protocol analyses were used. Results: Among the included 1034 patients, 762 were included in the conscious sedation group and 272 were included in the LA group. In the propensity score matched cohort, the rate of favorable outcome (90-day modified Rankin Scale score 0–2) was significantly lower in the LA group than in the conscious sedation group (40.0% versus 52.0%, matched relative risk=0.76 [95% CI, 0.60–0.97]), as well as the rate of successful reperfusion (modified Thrombolysis in Cerebral Infarction grade 2b–3; 76.6% versus 87.1%; matched relative risk=0.88 [95% CI, 0.79–0.98]). There was no difference in procedure time between the 2 groups. In the inverse probability of treatment weighting-propensity score-adjusted cohort, similar significant differences were found for favorable outcomes and successful reperfusion. In inverse probability of treatment weighting-propensity score-adjusted cohort, a higher rate of 90-day mortality and a lower parenchymal hematoma were observed after LA. The sensitivity analysis restricted to our per-protocol sample provided similar results in the matched- and inverse probability of treatment weighting-propensity cohorts. Conclusions: In the Endovascular Treatment in Ischemic Stroke registry mainly included patients in early time window (<6 hours), LA was associated with lower odds of favorable outcome, successful reperfusion, and higher odds of mortality compared with conscious sedation for mechanical thrombectomy of large vessel occlusion.