Background: The apolipoprotein E (APOE) epsilon 4 allele is a marker of adverse outcome following head injury and intracerebral hemorrhage. Transgenic animal data in a focal cerebral ischemia model suggest that the epsilon 4 allele increases infarct size and functional impairment. Objective: To determine if APOE genotype is associated with functional recovery from ischemic stroke. Design: Prospective study. Setting: Stroke service at a university teaching hospital. Patients: Patients with clinical and neuroimaging findings (computed tomography or magnetic resonance imaging) compatible with an acute ischemic stroke. Main Outcome: Functional outcome by Barthel index (BI) and modifed Rankin scale (mRS) was compared fur epsilon 3/epsilon 3 patients vs epsilon 4 carriers and vs epsilon 2 carriers at 1 and 3 months. Univariate predictors of 3-month outcome were examined in a multivariate analysis. Results: One hundred eighty nine patients were enrolled: 100 women, 89 men (mean+/-SD age, 69.4+/-11.0 years). There were 25 epsilon 2 alleles (frequency, 0.07), 292 epsilon 3 alleles (0.77), and 61 epsilon 4 alleles (0.16). Baseline National Institutes of Health Stroke Scale scores and Oxfordshire Community Stroke Project classifications were similar in all groups (epsilon 3/epsilon 3. epsilon 4, and epsilon 2 carriers). One-month (BI, P=.64; mRS, P=.59) and 3-month (BI, P=.87; mRS, P=.73) outcomes were not associated with possession of either epsilon 4 or the epsilon 2 allele. Baseline National Institutes of Health Stroke Scale scores (P<.001) and age (P=.002) were significant predictors of 3-month BI and mRS outcomes in multivariate analyses. Conclusions: Although there: is a robust influence of APOE polymorphism on functional recovery after some types of brain injury in humans, it does not exert a major influence on injury severity or functional recovery following ischemic stroke.