Hepatitis E virus (HEV) infection has been recognized an important insult of acute or acute-on-chronic liver failure (A(C)LF). This study aimed to identify the incidence, predictors and outcomes of A(C)LF in patients with hepatitis E. All patients diagnosed of hepatitis E between 2012 and 2018 in the tertiary hospital were retrospectively and consecutively analysed. Patients with hepatitis E who developed A(C)LF were enrolled as cases (HEV-LF) and controls were randomly selected from those who did not develop liver failure with 1:3 ratio in the same cohort. Eight hundred and nine patients were diagnosed with hepatitis E, among which 80 were identified with HEV-related liver failure (HEV-LF) with HEV as the solely acute aetiology of A(C)LF. Sequencing of HEV genome showed genotype (GT) 4 strains in all available serum samples. Hepatitis E patients with cirrhosis underwent higher risk to develop liver failure, compared to non-cirrhotic patients. Hydrothorax, respiratory infections, lower γ-glutamyl transferase, higher lactate dehydrogenase and alpha-foetoprotein were found to be independent predictors of A(C)LF in patients with hepatitis E. The 28-day and 90-day mortality for HEV-LF was 12.86% and 30.36% respectively. Renal injury and lower triglyceride were independent factors associated with 28-day mortality. Lower alanine aminotransferase and higher International normalized ratio were independent predictors of 90-day mortality. Patients with GT4 hepatitis E are at high risk to develop A(C)LF. Different CLD status impacted the incidence of HEV-LF distinctively. The identified variables shall help to identify HEV patients with high risk for developing liver failure and the risk for death. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.