An appropriate and timely management, including early diagnosis and accurate prognostication, is the mainstay for managed care of patients with acute ischemic stroke. Since red blood cell distribution width (RDW) was found to be an independent predictor of clinical outcomes in patients with thrombotic disorders, we designed a retrospective observational study to investigate whether the RDW value may also retain predictive significance in stoke patients undergoing thrombolytic therapy. This retrospective study was based on all patients admitted to the Emergency Department (ED) of the University Hospital of Verona (Italy) with a diagnosis of ischemic stroke, who underwent systemic thrombolysis between January 2013 and June 2015. The RDW value along with basal clinical characteristics was recorded at ED admission. The final study population consisted of 316 patients. A significant association was found between stroke severity (NIHSS score) and RDW (r = 0.322; p < 0.001). The median RDW value in patients with clinical improvement after thrombolysis was significantly lower than in patients without (13.4 vs. 14.1%; p < 0.001). The diagnostic accuracy (area under the curve) of RDW for predicting the lack of neurological improvement was 0.667. In univariate analysis, RDW >14.5% was associated with increased rate of no neurological improvement (odds ratio [OR], 2.38; 95% confidence interval [CI], 1.37-4.13), an association remaining significant also in multivariate analysis (OR, 1.85; 95% CI, 1.13-3.32). Survivor curve analysis showed that patients with RDW values ≥14.5% had a higher risk of 1-year mortality and shorter survival. These results suggest that RDW assessment at ED admission may provide valuable diagnostic and prognostic information in patients with acute ischemic stroke.