Background: Statins reportedly improve clinical outcomes for ischemic stroke patients. However, it is unclear whether the contribution of statin treatment varies depending on the severity of stroke. We sought to investigate the relationship between statin use and the outcome of acute first-ever ischemic stroke patients stratified by stroke severity. Methods: A total of 7,455 acute first-ever ischemic stroke patients without statin treatment before onset were eligible from the China National Stroke Registry. A National Institutes of Health Stroke Scale (NIHSS) score of 0 to 4 was defined as minor stroke, and a NIHSS score of >4 was defined as non-minor stroke. We analyzed the association between statin use during hospitalization and mortality as well as functional outcome (measured by a modified Rankin Scale score of 0-5) at 3 months after onset using multivariable logistic regression models. Results: A total of 3,231 (43.3%) patients received statin treatment during hospitalization. Multivariable analysis showed that statin use during hospitalization decreased mortality of ischemic stroke patients (OR, 0.51; 95% CI, 0.38-0.67), but did not improve poor functional outcomes (OR, 0.95; 95CI%, 0.81-1.11) at 3 months. The interaction between statin use and stroke severity was significant both in dependence and death outcome (P = 0.04 for dependence outcome, P = 0.03 for death outcome). After stratification by stroke severity, statin use during hospitalization decreased the mortality of stroke (OR, 0.44; 95% CI, 0.31-0.62) and poor functional outcome (OR, 0.73; 95% CI, 0.57-0.92) at 3 months in the non-minor stroke group. Conclusions: Statin use during hospitalization may improve the clinical outcome of acute first-ever ischemic stroke depending on the severity of stroke. Non-minor stroke patients may obtain benefit from statin treatment with improvements in poor functional outcomes and mortality.