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Introduction: Limited data exist regarding the relationship between acute infarct volume and health-related quality of life (HRQOL) measures after ischemic stroke. We sought to evaluate whether acute infarct volume predicts domain-specific Neuro-Quality of Life (Neuro-QoL) scores at 3 months.Methods: Between August 2012 and July 2014, we prospectively enrolled consecutive patients presenting with image-verified ischemic strokes and calculated acute infarct volume on diffusion-weighted imaging calculated using an automated algorithm. Clinical outcome scores at 3 months included modified Rankin score (mRS) and Neuro-QoL scores in 4 domains (general concerns, upper extremity, lower extremity, and executive function). We evaluated whether acute infarct volume predicted outcomes at 3 months using ordinal and linear regression as appropriate, adjusting for baseline mRS, payor status, NIHSS score, and post-stroke rehabilitation services.Results: Among 608 patients who met inclusion criteria (mean age 64.8 years, 50.5% females), the mean acute infarct volume was 6.59 mL and median initial NIHSS score was 2. At 3 months, 22.2% of subjects had mRS >1. In ordinal regression, acute infarct volume was independently associated with mRS at 3 months (p=0.027), adjusting for covariates. Table 1 describes the predictive models for each HRQoL measure along with the R2 value of the model and the fraction contributed by acute infarct volume.Discussion: Acute infarct volume, though significant, accounts for 1-5% of explained variance in HRQoL measures at 3 months after ischemic stroke. These data imply that other undiscovered biologic, clinical, and imaging factors may better predict post-stroke HRQoL than what is currently available.