Hepatitis E virus infection is a major cause of acute hepatitis, typically self-limiting but occasionally leading to liver failure. Understanding disease progression factors could inform prevention strategies. This study aimed to analyse the characteristics of a large cohort of hospitalised hepatitis E patients in Tianjin, China, and explore factors influencing their progression to liver failure. A total of 1279 hospitalised patients with hepatitis E were included in this cross-sectional study in Tianjin, China. Student's t-test and the Mann–Whitney U-test were used for comparisons. Multiple logistic regression analysis was used to explore the association. Among these 1279 patients, 107 (8.4%) developed liver failure. Patients with diabetes mellitus (DM) (95% confidence interval [CI] 1.150–2.887, p = 0.011), liver cirrhosis (95% [CI] 2.229–7.224, p < 0.001), and hepatitis B (95% [CI] 1.159–4.512, p = 0.017) were more likely to progress to liver failure. Hepatitis E patients with comorbid DM, liver cirrhosis, or hepatitis B virus co-infection have higher risks of developing liver failure. Hepatitis E vaccination may be recommended for these vulnerable patients to curb disease severity.