Introduction and Aims: The ANGEL-ASPECT trial demonstrated the effectiveness of endovascular therapy (EVT) in acute ischemic stroke (AIS) patients with large infarct. We did a secondary analysis to explore the efficacy of EVT according to Alberta Stroke Program Early Computed Tomography Score (ASPECT) and National Institutes of Health Stroke Scale (NIHSS). Methods: ANGEL-ASPECT trial was a randomized clinical trial involving patients with acute anterior-circulation large-vessel occlusion and an ASPECT score of 3-5 or an infarct-core volume of 70-100ml. Patients were randomly assigned to EVT or standard medical treatment (SMT) alone. We categorized patients based on the combination of ASPECT (≤3 or 4-5) and NIHSS (<20 or ≥20) into four groups: low ASPECT & low NIHSS; low ASPECT & high NIHSS; high ASPECT & low NIHSS and high ASPECT & high NIHSS. We assessed the efficacy of EVT using ordinal shift analysis of 90-day modified Rankin Scale (mRS). Results: Among 455 patients, the prevalence of the four groups were 190 (41.8%), 70 (15.4%), 157 (34.5%) and 38 (8.4%), respectively. A significant shift in the distribution of 90-days mRS toward better outcomes in favor of EVT was observed in patients with low ASPECT & low NIHSS (common OR [cOR], 2.25; 95% CI, 1.34-3.76; P=0.002), and high ASPECT & low NIHSS (cOR, 2.30; 95% CI, 1.31-4.05; P=0.004), but not in other two groups with high NIHSS (all P >0.05). Conclusions: EVT was associated with better outcomes in AIS patients with large infarct and mild-to-moderate stroke severity (NIHSS <20), but not in those with severe stroke severity (NIHSS ≥20). Stroke severity should be considered when planning EVT for AIS patients with large infarcts.