We aimed to investigate the impact of smoking status on clinical severity in patients with ischemic stroke event (IS). Patients were prospectively identified among residents of the city of Dijon, France (ca. 151,000 inhabitants), using a population-based registry, between 2006 and 2011. Demographic and clinical data were recorded. The initial clinical severity was quantified by the means of the National Institutes of Health Stroke Scale (NIHSS). Multivariable ordinal logistic regression was used to assess the effect of smoking status on severity. Among the 1,056 recorded patients with IS, data about smoking status were available for 973 (92.1%), of whom 658 (67.3%) were non-smokers, 187 (19.2%) were current smokers, and 128 (13.2%) were former smokers. Compared with non-smoking, former smoking was associated with less severe IS (OR 0.55; 95% CI 0.38-0.82, p = 0.003), whereas this association was not found for current smokers (OR 0.97; 95% CI 0.69-1.36, p = 0.856). Further work is needed to understand the underlying mechanisms of this finding.