Background: Liver injury is common and also can be fatal, particularly in severe or critical patients with coronavirus disease 2019 (COVID-19). However, there is lack of an in-depth investigation into the risk factors of liver injury and into the effective measures to prevent subsequent mortality risk. Methods: A retrospective cohort study of 440 consecutive patients with relatively severe COVID-19 between January 28 and March 9, 2020 in Tongji Hospital, Wuhan, China was performed. Data on clinical features, laboratory parameters, medications and prognosis were collected. Results: COVID-19-associated liver injury more frequently occurred in patients aged ≥65 years, or female, or with other comorbidities, decreased lymphocyte count, elevated D-dimer or serum ferritin (all p values<0.05). The disease severity of COVID-19 was an independent risk factors of livery injury (OR 2.86; 95% CI 1.78 to 4.59 in severe patients and 13.44; 95% CI, 7.21 to 25.97 in critical patients). The elevated levels of on-admission aspartate aminotransferase (AST) and total bilirubin (TBIL) indicated the increased mortality risk (both p values <0.001). Using intravenous nutrition or antibiotics increased risk of COVID-19-associated liver injury. Hepatoprotective drugs tended to be of assistance to treat the liver injury and improve the prognosis of patients with COVID-19-associated liver injury. Conclusions: More intensive monitoring with AST or TBIL is recommended for COVID-19 patients, especially aged ≥65 years, or female, or with other comorbidities. Drug hepatotoxicity of antibiotics and intravenous nutrition should be alert for COVID-19 patients.