Background In the setting of acute ischemic stroke (AIS), leukocytosis has been shown to be an indicator of inflammatory response. Although leukocytosis on admission has been shown to correlate with initial stroke severity in AIS patients, no work has been done to assess if there are differences in transient or persistent leukocytosis in patients without infection. The objective of this study is to determine the clinical significance of persistent versus transient leukocytosis during the early phase of AIS. Methods Patients who presented with AIS to our center within 48 hours of symptom onset between July 2008 and June 2010 were retrospectively identified by chart review. Patients were included if they had leukocytosis on admission (defined as white blood cell count >11,000/μL based on laboratory reference range values). A logistic regression model was used to evaluate persistent leukocytosis (leukocytosis 48 hours after admission) as a predictor of several outcome measures, including good functional outcome (discharge modified Rankin Scale score of 0-2). Marginal effects were used to estimate the probability of poor functional outcome. Results Of the 438 patients screened, 49 had leukocytosis on admission and of those 24 (49%) had persistent leukocytosis. NIHSS score correlated significantly with persistence of leukocytosis (r =.306; P =.0044). More people with transient leukocytosis (leukocytosis lasting <48 hours) had a good functional outcome (44% versus 16%; P =.006). After adjusting for baseline NIHSS score, persistent leukocytosis was not a significant independent predictor of good functional outcome, but showed an association (OR, 2.5; 95% CI,.562-10.7; P =.2322). Persistent leukocytosis after adjusting for age and NIHSS score at admission is associated with a poor functional outcome, but it is not statistically significant (OR, 2.43; 95% CI,.59-9.87; P =.2151). After controlling for age and NIHSS score on admission, for patients with persistent leukocytosis, the probability of having poor functional outcome at discharge was increased by 16 percentage points. Conclusions Persistent leukocytosis is associated with higher baseline NIHSS scores. Persistent leukocytosis is tightly linked with baseline stroke severity and is associated with poor patient outcomes. Our study found that patients with persistent leukocytosis are more likely to present with severe strokes and maintain a high NIHSS score at 24 hours after admission, unlike patients without leukocytosis or patients with transient leukocytosis. Furthermore, it appears that persistent leukocytosis outside the setting of an infection negatively impacts the short-term functional outcome of AIS patients. Identifying patients with persistent leukocytosis could help to prognosticate and target patients that may benefit from future anti-inflammatory interventions. © 2014 by National Stroke Association.