Background: The benefit of distinguishing between disabling versus nondisabling deficit in mild acute ischemic stroke due to endovascular thrombectomy-targetable vessel occlusion (EVT-tVO; including anterior circulation large and medium-vessel occlusion) is unknown. We compared safety and efficacy of acute reperfusion treatments in disabling versus nondisabling mild EVT-tVO. Methods: From the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register, we included consecutive acute ischemic stroke patients (2015–2021) treated within 4.5 hours, with full NIHSS items availability and score ≤5, evidence of intracranial internal carotid artery, M1, A1-2, or M2-3 occlusion. After propensity score matching, we compared efficacy (3-month modified Rankin Scale score of 0–1, modified Rankin Scale score of 0–2, and early neurological improvement) and safety (nonhemorrhagic early neurological deterioration, any intracerebral or subarachnoid hemorrhage, symptomatic intracranial hemorrhage, and death at 3-month) outcomes in disabling versus nondisabling patients—adopting an available definition. Results: We included 1459 patients. Propensity score matched analysis of disabling versus nondisabling EVT-tVO (n=336 per group) found no significant differences in efficacy (modified Rankin Scale score 0–1: 67.4% versus 71.5%, P =0.336; modified Rankin Scale score 0–2: 77.1% versus 77.6%, P =0.895; early neurological improvement: 38.3% versus 44.4%, P =0.132) and safety (nonhemorrhagic early neurological deterioration: 8.5% versus 8.0%, P =0.830; any intracerebral hemorrhage or subarachnoid hemorrhage: 12.5% versus 13.3%, P =0.792; symptomatic intracranial hemorrhage: 2.6% versus 3.4%, P =0.598; and 3-month death: 9.8% versus 9.2%, P =0.844) outcomes. Conclusions: We found similar safety and efficacy outcomes after acute reperfusion treatment in disabling versus nondisabling mild EVT-tVO; our findings suggest to adopt similar acute treatment approaches in the 2 groups. Randomized data are needed to clarify the best reperfusion treatment in mild EVT-tVO.