Background and Aims The HMG-CoA reductase inhibitors (statins) are widely prescribed for patients with hyperlipidemia. Liver injury is one of the most common adverse drug reaction (ADR) of statins. Severe liver injury can cause acute liver failure and even death. The aim of this study is to report the risk factors of severe statin induced liver injury (SILI). Methods From the database of Shandong ADR Monitoring Center and Outpatients and inpatients in our hospital, SILI cases reported from 2013 to 2021 were extracted and screened. The diagnostic criteria of SILI, the inclusion and exclusion criteria of severe and general SILI were established separately. After the SILI cases were selected and confirmed. The socio-demographic and clinical characteristics were collected, including gender, age, weight, latency (the time interval from statin use to the the initial liver injury), past history (such as smoking, drinking, drug allergy and liver disease, etc), drug combination, statins category, route of administration, drug dosage form. Single factor chi-square test and multi-factor unconditional logistic regression analysis were used to analyze the influencing factors of severe SILI. Results From 1391 reported cases, 1211 met SILI diagnostic criteria, of which 157 were severe SILI and 964 were general SILI. Univariate analysis showed that age, drug combination, statin category were the influencing factors of severe SILI (P<0.1). Multivariate logistic analysis showed that drug combination and statin category were the influencing factors of severe SILI (P<0.05). Conclusion Atorvastatin caused the most serious SILI, and its risk is 1.77 times higher than rosuvastatin. The serious SILI risk of drug combination was 2.08 times higher than statin alone. The patient with these factors should be monitored intensively during clinical treatment, to ensure their medication safety.