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Background: Early prognostication of long-term outcomes following ischemic stroke can facilitate medical decision-making. We hypothesized that the 24-hour National Institute of Health Stroke Scale (NIHSS) predicts 3-month clinical outcomes in anterior circulation stroke., Methods: Secondary analyses of the Interventional Management of Stroke 3 (IMS3) and intravenous tissue plasminogen activator (IV tPA) for acute ischemic stroke [National Institute of Neurological Diseases and Stroke (NINDS) IV tPA] trials were performed. In participants with documented 24-hour NIHSS and 3-month Modified Rankin Scale (mRS), the predictive power of the 24-hour NIHSS and 24-hour NIHSS improvement for 3-month outcomes [mRS 0-2 and Barthel Index (BI) ≥95] was assessed. Percentages of good outcome (mRS 0-2 or BI ≥95) at 3, 6, and 12 months and mean quality of life (EQ5D™) index at 3 months across 24-hour NIHSS quartiles were compared., Results: The majority of the study participants were included (IMS3 n = 587/656, NINDS IV tPA n = 619/624). The 24-hour NIHSS was correlated with 3-month mRS (R = 0.73) with excellent predictive power for mRS 0-2 [area under the curve (AUC) = 0.91] and BI ≥95 (AUC = 0.9) in both cohorts. A model with the 24-hour NIHSS alone correctly classified 82-84% of patients in both cohorts. The percentages of good outcomes at 3-12 months across 24-hour NIHSS quartiles were similar in both cohorts. mRS 0-2 was achieved by 75.6-77.7% of patients with 24-hour NIHSS ≤11 but by only 1.4-3.6% with 24-hour NIHSS ≥20. The EQ5D index at 3 months varied among NIHSS 0-4 (mean 0.86 ± 0.16), 5-11 (0.77 ± 0.18), and 12-19 (0.59 ± 0.26) quartiles., Conclusions: The 24-hour NIHSS strongly predicts long-term stroke outcomes and is associated with quality of life. Its easy availability, reliability, and validity support its use as an early prognostic marker and surrogate of clinical outcome in ischemic stroke.