A previous study showed early statin administration in patients with acute ischemic stroke (AIS) was associated with a lower risk of early-onset seizure (ES), which is a high risk of epilepsy, but this retrospective study design may not have eliminated confounding factor effects. We aimed to verify the determinants and prognostic significance of ES and clarify the effects of statin administration. Consecutive AIS patients without a history of epilepsy were enrolled. The relationship between ES (within 7 days of index-stroke) and statin treatment was assessed using multivariate and propensity scores (PS). Of 2,969 patients with AIS, 1,623 (54.6%) were treated with statin, and 66 (2.2%) developed ES. In logistic regression models, cortical stroke lesion [odds ratio (OR), 2.82; 95% confidence interval (CI), 1.29-7.28) and pre-morbid modified Rankin Scale (per 1 point) (OR, 1.39; 95% CI, 1.18-1.65) were higher risks for ES, while statin significantly reduced the risk of ES (OR, 0.44; 95% CI, 0.24-0.79). In accordance with PS-matching, statin treatment produced consistent results for ES after adjusting by inverse probability of treatment-weighting PS (OR, 0.41; 95% CI, 0.22-0.75). In conclusion, as previously, statin treatment was independently associated with a lower risk of ES in AIS.