Background: Acute-on-chronic liver failure (ACLF) which has a high mortality, is frequent during the course of severe alcoholic hepatitis (SAH). Maddrey Discriminant Function (MDF), as a prognostic score special for alcoholic hepatitis, does not show a good prognostic value in ACLF associated with alcoholic liver disease (ALD). It is well-known that the serum levels of vitamin B12 (vitB12) and folic acid, as important substances in the methionine metabolism pathway, were altered in the patients of ALD and may impact on the outcomes of these patients. In this study, the relationship between vitB12 levels, erythrocyte parameters and severity of liver disease in patients with ALD was evaluated to improve the prediction of short-term prognosis in ALD-ACLF by combining with the valuable indexes. Methods: 139 ALD patients were included in the cross-sectional cohort and grouped according to different prognostic scores, the factors that affect the scores were collected and statistically analyzed. In addition, a retrospective cohort of 79 patients was investigated to reveal the correlation between vitB12 and Mean Corpuscular Volume (MCV) with the 28‐day mortality of ALD-ACLF. SPSS (20.0) and Medcalc (15.2.2) were used to perform statistical analyses. T-test, chi-square test or Fisher's as well as multivariate Logistic regression analysis were used. The ROC curve was plotted for relevant indicators, and the area under curve (AUC), cut-off value, sensitivity and specificity were calculated. Results: Patients with high scores in MDF, Model for End-stage Liver Disease (MELD) and Age-INR-Bilirubin-Creatine (AIBC), had higher vitB12 levels than those with low scores(1264.78±623.52 VS 634.04±426.57, P<0..001; 1498.47±640.48 VS 750.83±501.95, P<0.001; 1183.71±703.42 VS 813.24±553.32, P<0.05); MCV levels were higher in patients with high MDF scores (105.43±13.02 VS 99.24±13.52, P<0.05). The AUC of a new model of MDF combined with vitB12 and MCV for 28‐day mortality was 0.802, which was significantly higher than that of vitB12, MCV, and MDF scores.Conclusions: High levels of vitB12, MCV and the severity of ALD have a statistically significant correlation. MDF combined with vitB12 and MCV have been showed a good specificity to predict 28‐day mortality in ACLF-ALD and it may be a new promising prognostic model in ACLF-ALD.