Background Outcomes after stroke as a result of large‐vessel occlusion in patients with prestroke disability were compared between endovascular therapy (EVT) and medical management. Methods and Results Of 2420 patients with acute stroke with large‐vessel occlusion in a prospective, multicenter, nationwide registry in Japan, patients with prestroke modified Rankin Scale scores 2 to 4 with occlusion of the internal carotid artery, or M1 of the middle cerebral artery were analyzed. The primary effectiveness outcome was the favorable outcome, defined as return to at least the prestroke modified Rankin Scale score at 3 months. Safety outcomes included symptomatic intracranial hemorrhage. A total of 339 patients (237 women; median 85 [interquartile range (IQR), 79–89] years of age; median prestroke modified Rankin Scale score of 3 [IQR, 2–4]) were analyzed. EVT was performed in 175 patients (51.6%; mechanical thrombectomy, n=139). The EVT group was younger ( p <0.01) and had lower prestroke modified Rankin Scale scores ( p <0.01) than the medical management group. The favorable outcome was seen in 28.0% of the EVT group and in 10.9% of the medical management group ( p <0.01). EVT was associated with the favorable outcome (adjusted odds ratio, 3.01; 95% CI, 1.55–5.85; mixed effects multivariable model with inverse probability of treatment weighting). Symptomatic intracranial hemorrhage rates were similar between the EVT (4.0%) and medical management (4.3%) groups ( p =1.00). Conclusions Patients who underwent EVT showed better functional outcomes than those with medical management. Given proper patient selection, withholding EVT solely on the basis of prestroke disability might not offer the best chance of favorable outcome. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.