Background and Purpose—Intravenous thrombolysis (IVT) followed by mechanical thrombectomy (MT) improves functional outcome in patients with ischemic stroke related to proximal-vessel occlusion in the anterior circulation. Whether MT alone is as effective as IVT/MT remains controversial. We aimed at evaluating the influence of IVT in patients with large anterior circulation artery occlusion treated with MT.Methods—We did a prospective observational cohort study in patients with stroke related to large anterior circulation artery occlusion treated by MT who were admitted to Lille University Hospital, Lille, France. We evaluated the influence of IVT on favorable functional outcome (defined as a modified Rankin Scale score 0–2 or similar to the prestroke modified Rankin Scale) and on mortality at month 3. Between-group comparisons in outcomes were adjusted for prespecified confoundors by using a propensity score–adjusted approach.Results—From January 2012 to January 2017, we included 485 patients (median age, 68 years; 46% men; 348 [72%] in the IVT/MT group; 137 [28%] in the MT group). In MT group, 22% of patients had a favorable outcome versus 35% in IVT/MT group (adjusted relative risk, 1.76; 95% confidence interval, 1.23–2.55). Mortality within 3 months occurred less frequently in IVT/MT group (14% versus 32%; adjusted relative risk, 0.46; 95% confidence interval, 0.31–0.70). Successful reperfusion (Thrombolysis in Cerebral Infarction scale 2b-3) was more frequent in IVT/MT group (75% versus 60%; adjusted relative risk, 1.30; 95% confidence interval, 1.11–1.53). There was no difference between groups on hemorrhagic complications.Conclusions—In this population, previous IVT improved functional outcome and survival at 3 months in patients treated by MT. While waiting for randomized controlled trials, this result encourages not to avoid IVT before MT.