Background: Neurologic deterioration (ND) after ischemic stroke has been shown to impact short-term functional outcome and is associated with in-hospital mortality. Methods: Patients with acute ischemic stroke who presented between July 2008 and December 2010 were identified and excluded for in-hospital stroke, presentation >48 hours since last seen normal, or unknown time of last seen normal. Clinical and laboratory data, National Institutes of Health Stroke Scale (NIHSS) scores, and episodes of ND (increase in NIHSS score ≥2 within a 24-hour period) were investigated. Results: Of the 596 patients screened, 366 were included (median age 65 years; 42.1% female; 65.3% black). Of these, 35.0% experienced ND. Patients with ND were older (69 v 62 years; P <.0001), had more severe strokes (median admission NIHSS score 12 v 5; P <.0001), carotid artery stenosis (27.0% v 16.8%; P =.0275), and coronary artery disease (26.0% v 16.4%; P =.0282) compared to patients without ND. Patients with ND had higher serum glucose on admission than patients without ND (125.5 v 114 mg/dL; P =.0036). After adjusting for crude variables associated with ND, age >65 years, and baseline NIHSS score >14 remained significant independent predictors of ND. In a logistic regression analysis adjusting for age and serum glucose, each 1-point increase in admission NIHSS score was associated with a 7% increase in the odds of ND (odds ratio 1.07; 95% confidence interval 1.04-1.10; P <.0001). Conclusions: Older patients and patients with more severe strokes are more likely to experience ND. Initial stroke severity was the only significant, independent, and modifiable risk factor for ND, amenable to recanalization and reperfusion. © 2013 by National Stroke Association.