Background/AimsHepatitis E virus (HEV)-triggered acute-on-chronic liver failure (ACLF) has unacceptably high short-term mortality. However, it is unclear whether the existing predictive scoring models are applicable to evaluate the prognosis of HEV-triggered ACLF.MethodsWe screened datasets of patients with HEV-triggered ACLF from a regional tertiary hospital for infectious diseases in Shanghai, China, between January 2011 and January 2021. Clinical and laboratory parameters were recorded and compared to determine a variety of short-term mortality risk factors, which were used to develop and validate a new prognostic scoring model.ResultsOut of 4952 HEV-infected patients, 817 patients with underlying chronic liver disease were enrolled in this study. Among these, 371 patients with HEV-triggered ACLF were identified and allocated to the training set (n = 254) and test set (n = 117). The analysis revealed that hepatic encephalopathy (HE), ascites, triacylglycerol and apolipoprotein A (apoA) were associated with 90-day mortality (P< 0.05). Based on these significant indicators, we designed and calculated a new prognostic score = 0.632 × (ascites: no, 1 point; mild to moderate, 2 points; severe, 3 points) + 0.865 × (HE: no, 1 point; grade 1–2, 2 points; grade 3–4, 3 points) − 0.413 × triacylglycerol (mmol/L) − 2.171 × apoA (g/L). Compared to four well-known prognostic models (MELD score, CTP score, CLIF-C OFs and CLIF-C ACLFs), the new scoring model is more accurate, with the highest auROCs of 0.878 and 0.896, respectively, to predict 28- and 90-day transplantation-free survival from HEV-triggered ACLF. When our model was compared to COSSH ACLF IIs, there was no significant difference. The test data also demonstrated good concordance.ConclusionsThis study is one of the first to address the correlation between hepatitis E and serum lipids and provides a new simple and efficient prognostic scoring model for HEV-triggered ACLF.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12944-023-01826-y.