RATIONALE: Mechanical thrombectomy (MT), the standard of care for acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO), is generally not offered to patients with large baseline infarct (core). Recent studies demonstrated MT benefit in patients with anterior circulation stroke and large core (i.e. Alberta Stroke Program Early Computed Tomography Score, ASPECTS 3-5). However, its benefit in patients with the largest core (ASPECTS 0-2) remains unproven. AIM: To compare the efficacy and safety of MT plus best medical treatment (BMT) and of BMT alone in patients with ASPECTS 0-5 (baseline computed tomography (CT) or magnetic resonance imaging (MRI)) and anterior circulation LVO within 7 h of last-seen-well. SAMPLE SIZE ESTIMATE: To detect with a two-sided test at 5% significance level (80% power) a common odds ratio of 1.65 for 1-point reduction in the 90-day modified Rankin Scale (mRS) score in the MT + BMT arm versus BMT arm and to anticipate 10% of patients with missing primary endpoint, 450 patients are planned to be included by 36 centers in France, Spain, and the United States. METHODS AND DESIGN: LArge Stroke Therapy Evaluation (LASTE) is an international, multicenter, Prospectively Randomized into two parallel (1:1) arms, Open-label, with Blinded Endpoint (PROBE design) trial. Eligibility criteria are diagnosis of AIS within 6.5 h of last-seen-well (or negative fluid-attenuated inversion recovery (FLAIR) if unknown stroke onset time), ASPECTS 0-5 (ASPECTS 4-5 for ⩾80-year-old patients), and LVO in the anterior circulation (intracranial internal carotid artery (ICA) and M1 or M1-M2 segment of the middle cerebral artery (MCA)). STUDY OUTCOMES: The primary endpoint is the day-90 mRS score distribution (shift analysis) with mRS categories 5 and 6 coalesced into one category. Secondary endpoints include day-180 mRS score, rates of 90-day and 180-day mRS score = 0-2 and 0-3, rate of decompressive craniectomy, the National Institutes of Health Stroke Scale (NIHSS) score change, revascularization and infarct volume growth at 24 h, and quality of life at day 90 and 180. Safety outcomes (90-day all-cause mortality, procedural complications, symptomatic intracerebral hemorrhage, and early NIHSS score worsening) are recorded. A dynamic balanced randomization (1:1) is used to distribute eligible patients into the experimental arm and control arm, by incorporating the center and these pre-specified factors: baseline ASPECTS (0-3 vs 4-5), age (⩽70 vs >70 years), baseline NIHSS (<20 vs ⩾20), intravenous thrombolysis (no vs yes), admission mode (Drip-and-Ship vs Mothership), occlusion site (intracranial ICA vs MCA-M1 or M1-M2), intravenous fibrinolysis (no vs yes), and last-seen-well to randomization time (0-4.5 vs >4.5-6.5 h). DISCUSSION: The LASTE trial will determine MT efficacy and safety in patients with ASPECTS 0-5 and LVO in the anterior circulation. TRIAL REGISTRATION: LASTE Trial NCT03811769.