We aimed to characterize the association between pretreatment lesional volume measured on diffusionweighted images and functional outcome, and estimate the impact on thrombectomy efficacy for ischemic stroke with anterior proximal intracranial arterial occlusion. Methods: Anterior circulation ischemic stroke patients who had pretreatment diffusion-weighted imaging in the THRACE study were included. Lesional volume was semiautomatically segmented. Logistic regression was applied to model clinical outcome as a function of lesional volume. Outcomes included functional independence (modified Rankin Scale [mRS] 0-2), degree of disability (ordinal mRS 0-6), and mortality at 3 months. Results: Of 298 included patients, with median lesional volume 17.2ml (interquartile range [IQR], 9.2-51.8) and median mRS 2 (IQR, 1-4), 51.0% achieved functional independence. Increased lesional volume was an independent predictor for a lower probability of functional independence (odds ratio [OR], 0.90 [95% confidence interval {CI}, 0.81-0.99] per 10ml; p < 0.001), a less favorable degree of disability (common OR, 0.86 [95% CI, 0.81-0.90] per 10ml; p < 0.001), and a higher mortality rate (OR, 1.21 [95% CI, 1.08-1.37] per 10ml; p < 0.001). For additional thrombectomy, the number of patients needed to treat to achieve functional independence in 1 patient increased with lesional volume (10 for a volume of 80ml; 15 for 135ml). No significant treatment-by-dichotomized volume interaction for functional independence and mortality was observed. Interpretation: Pretreatment lesional volume is an independent predictor for functional outcome in acute ischemic stroke with proximal intracranial occlusion. The clinical benefit of adding mechanical thrombectomy to thrombolysis decreased with the increase of lesional volume.