BACKGROUND: Acute-on-chronic liver failure (ACLF) is a liver disease based on chronic liver disease, which is significantly influenced by clinical treatment regimen and disease status, and despite the existence of multiple prognostic assessment indicators for ACLF, the overall sensitivity and accuracy are relatively low. AIM: To investigate the prognostic value of the combined detection of alpha-fetoprotein (AFP), plasma prothrombin activity (PTA), and serum prealbumin (PA) in ACLF. METHODS: This retrospective study included 87 patients with ACLF admitted from February 2021 to February 2023 and categorized them into the survival ( RESULTS: AFP, PTA, and PA levels were markedly decreased in the death group than in the survival group ( CONCLUSION: The combined detection of AFP, PTA, and PA levels demonstrates favorable diagnostic value for the short-term prognosis of patients with ACLF, featuring high sensitivity and specificity.