Objective To explore the prognostic factor and its predictive value of patients with Wilson disease-related acute-on-chronic liver failure (WD-ACLF). Methods The clinical data of 70 patients diagnosed as WD-ACLF admitted to the Department of Encephalopathy of the First Affiliated Hospital of Anhui University of Chinese Medicine from January 1, 2017 to January 1, 2022 were retrospectively collected. According to the 12-week prognosis, patients were divided into survival group (n=36) and death group (n=34). The data of the two groups were analyzed by univariate and multivariate logistic analysis to screen the prognostic risk factors and evaluate their predictive value. The model coefficient is omnibus tested, and the model-fitting degree is evaluated by the Hosmer-Lemeshow test. ROC curve was used to analyze the prognostic value for WD-ACLF between the new model and chronic liver failure-sequential organ failure assessment (CLIF-SOFA) score, model for end-stage liver disease (MELD) score and Child-Turcotte-Pugh (CTP) score. Results A total of 70 WD-ACLF patients were enrolled in present study, including 36 cases in survival group [22 males and 14 females with median age of 30.0 (17.3, 40.0)] and 34 cases in death group [25 males and 9 females with median age of 34.0 (28.8, 41.0)]. Univariate analysis showed that the course of disease, prothrombin time (PT), activated partial thromboplastin time (APTT) were shorter in survival group than that in death group, the white blood cells (WBC), international normalized ratio (INR), aspartate transaminase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), creatinine (Cre) and ceruloplasmin (CER) levels and the proportion of infection, ascites, and upper gastrointestinal bleeding were lower in survival group than those in death group, however, the proportion of infection, ascites and upper digestive bleeding in the survival group were lower than those in the death group. Meanwhile, the red blood cells (RBC), hemoglobin (Hb), Na⁺ and total cholesterol (TC) level in the survival group were higher than those in the death group (P<0.05 or P<0.01). The results of multivariate logistic regression analysis showed that disease course (OR=1.176, 95%CI 1.043-1.325), INR (OR=7.635, 95%CI 1.767-32.980), TBIL (OR=1.012, 95%CI 1.003-1.021), and upper gastrointestinal bleeding (OR=11.654, 95%CI 1.029-131.980) were independent risk factors affecting the prognosis of WD-ACLF (P<0.05). Based on the results of logistic regression analysis, a joint model for predicting the prognosis of WD-ACLF was established. The AUC of the model for evaluating the prognosis of WD-ACLF was 0.941, which was greater than the CLIF-SOFA score (AUC=0.802), MELD score (AUC=0.897), and CTP score (AUC=0.722). Conclusions The course of disease, TBIL, INR, and upper gastrointestinal bleeding are risk factors that affect the prognosis of WD-ACLF. The prognosis model established based on this can more accurately predict the prognosis of WD-ACLF patients, and its predictive value is superior to CLIF-SOFA score, MELD score, and CTP score.