Objectives To investigate the risk factors, clinical features, and clinical outcomes of severe cerebral infarction (SCI), and explore the association between different risk factors and outcomes in SCI. Methods We prospectively registered consecutive cases of acute ischemic stroke at the neurological wards of West China Hospital, Sichuan University from January 1st, 2008 to May 27th, 2013. Patients with ischemic stroke within 30 days of symptom onset were included. SCI was defined as the score of National Institutes of Health Stroke Scale greater than 15. Data were collected on clinical and biological variables, risk factors for stroke and the presence of comorbidities. The data management and analysis were performed with the SPSS 16.0 package. Univariate and multivariate analysis were used to analyze the predictors of SCI and its outcomes. Results Of the 3 364 enrolled cases, 348 (10.3%) were SCI. Compared with non-SCI (NSCI), SCI patients were older, with a lower proportion of males, higher NIHSS scores, lower Glasgow Coma Scale (GCS) scores, and higher proportions of previous heart disease history and previous stroke history, and lower hemoglobin levels on admission. SCI group had a greater proportion of large-artery atherosclerosis (LAA) and cardioembolism (CE) and less proportion of small artery occlusive infarction. After adjustment for the confounders, age [odds ratio (OR)=1.020, 95% confidence interval (CI) (1.010, 1.031), P<0.001], LAA [OR=1.442, 95%CI (1.062, 1.958), P=0.019], and CE [OR=1.919, 95%CI (1.319, 2.793), P=0.001] were independently associated with SCI. The case fatality and case fatality or disability with SCI were 32.1% and 83.3% at the end of 3 months, and 41.8% and 79.3% at the end of 1 year. Among different types, patients with undetermined type had the highest mortality rate, with patients with LAA being the lowest (P≤0.001). There was no significant association between TOAST type and the rate of fatality or disability. Multiple factor analysis showed that the most important independent predictive factor of prognosis was age. Meanwhile, sex and previous stroke history were also the independent predictive factors for death at the 3rd month. Hyperlipidemia, valvular heart disease, and GCS score on admission were independent predictive factors for death/disability at the 3rd month. Conclusions Our study indicates that patients with SCI accounted for 10.3% of acute ischemic stroke. The case fatality or disability in SCI patients are higher than those in NSCI patients. The old age, LAA and CE are independent predictive factors of SCI. Age is the most important prognostic factor of patients with SCI.