BACKGROUND: This study aimed to investigate whether net water uptake (NWU) is associated with 3-month catastrophic functional outcome (modified Rankin Scale score, 5–6) and to develop predictive models with preprocedural factors, including NWU, in patients with large infarcts who underwent endovascular thrombectomy. METHODS: This multicenter observational cohort study conducted in Korea included patients with anterior circulation stroke and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of ≤5 receiving endovascular thrombectomy between 2015 and 2023. NWU, a quantitative imaging biomarker reflecting the degree of hypoattenuation on noncontrast computed tomography, was measured across the entire ASPECTS region (ASPECTS10-NWU), and its association with catastrophic functional outcome was assessed using a mixed-effects logistic regression model, adjusting for age, sex, prestroke modified Rankin Scale score, baseline National Institutes of Health Stroke Scale score, baseline ASPECTS, onset-to-baseline noncontrast computed tomography time, and intravenous tissue-type plasminogen activator, with hospital included as a random effect. Moreover, a predictive model has been developed with preprocedural factors that were significant covariates from the mixed-effects logistic regression analysis. RESULTS: A total of 255 patients were included (mean age, 71.0±12.6 years; 54.9% male). The median ASPECTS10-NWU was 3.0% (interquartile range, 1.9%–4.1%). Higher ASPECTS10-NWU was independently associated with catastrophic functional outcome (adjusted odds ratio, 1.70 [95% CI, 1.33–2.17]; P <0.001). The model integrating ASPECTS10-NWU with preprocedural variables suggested predicted catastrophic functional outcome probabilities; as ASPECTS10-NWU and baseline National Institutes of Health Stroke Scale score increased, the marginal probability of catastrophic functional outcome increased in all age (<80 and ≥80 years) and prestroke modified Rankin Scale score (0–1 and 2–4) groups, with the patients aged ≥80 years and with prestroke modified Rankin Scale score of 2 to 4 having higher outcome probability. CONCLUSIONS: Elevated ASPECTS10-NWU is strongly associated with catastrophic functional outcome in patients with large infarcts treated with endovascular thrombectomy. Integrating the ASPECTS10-NWU with clinical variables may provide patient-specific prognostication that may assist clinicians in decision-making for endovascular thrombectomy in large infarcts.