Background Neurologic deterioration (ND) occurs in one third of patients with ischemic stroke and contributes to morbidity and mortality in these patients. Etiologies of ND and clinical outcome according to ND etiology are incompletely understood. Methods We conducted a retrospective investigation of all patients with ischemic stroke admitted to our center (July 2008 to December 2010), who were known to be last seen normal less than 48 hours before arrival. First-time episodes of ND during hospitalization were collected in which a patient experienced a 2-point increase or more in National Institutes of Health Stroke Scale score within a 24-hour period. Proposed etiologies of reversible ND include infectious, metabolic, hemodynamic, focal cerebral edema, fluctuation, sedation, and seizure, whereas new stroke, progressive stroke, intracerebral hemorrhage, and cardiopulmonary arrest were nonreversible. Results Of 366 included patients (median age 65 years, 41.4% women, 68.3% black), 128 (34.9%) experienced ND (median age 69 years, 42.2% women, 68.7% black). Probable etiologies of ND were identified in 90.6% of all first-time ND events. The most common etiology of ND, progressive stroke, was highly associated with poor outcome but not death. Etiologies most associated with mortality included edema (47.8%), new stroke (50%), and intracerebral hemorrhage (42.1%). Conclusions In the present study, the authors identified probable etiologies of ND after ischemic stroke. Delineating the cause of ND could play an important role in the management of the patient and help set expectations for prognosis after ND has occurred. Prospective studies are needed to validate these proposed definitions of ND. © 2013 Elsevier B.V. All rights reserved.