Objective To investigate the value of Charlson comorbidity index (CCI) in predicting the short- and long-term risks of death in patients with acute-on-chronic liver failure (ACLF). Methods A total of 317 patients with ACLF who attended The First Hospital of Lanzhou University from December 1, 2016 to December 1, 2021 were enrolled, and according to their prognosis, they were divided into death group with 169 patients and survival group with 148 patients. The two groups were analyzed in terms of clinical data and follow-up data. The group t -test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. The univariate and multivariate Cox proportional-hazards regression model analyses were used to investigate the influencing factors for the prognosis of ACLF patients. The Kaplan-Meier method was used to plot survival curves, and the Log-rank test was used for comparison of survival time between patients with different CCI scores. The receiver operating characteristic (ROC) curve was used to evaluate the performance of CCI and other indices in assessing the prognosis of ACLF patients. Results Among the 317 patients, there were 225 (71.0%) male patients. There were significant differences between the death group and the survival group in age, hemoglobin, white blood cell count, total bilirubin, albumin, Model for End-Stage Liver Disease (MELD) score, prothrombin time activity, CCI, age-adjusted Charlson co-morbidity index (ACCI), and follow-up time (all P < 0.05). The multivariate Cox regression analysis showed that the CCI (hazard ratio [ HR ]=1.351, 95% confidence interval [ CI ]: 1.112-1.641, P =0.002), ACCI ( HR =1.200, 95% CI : 1.011-1.423, P =0.037), and MELD score ( HR =1.076, 95% CI : 1.054-1.099, P < 0.001) were independent risk factors for the prognosis of ACLF patients. Based on CCI score, the patients were divided into CCI ≤4 group with 167 patients, CCI=5 group with 64 patients, and CCI ≥6 group with 86 patients, with a 3-year mortality rate of 26.5%, 83.2%, and 96.9%, respectively, and there was a significant difference in survival time between any two groups after 3 years of follow-up and at the time of follow-up till September 2022 (all P < 0.001). CCI, ACCI, and MELD scores had an area under the ROC curve of 0.845, 0.811, and 0.790, respectively, in predicting the prognosis of ACLF patients. Conclusion As commonly used comorbidity assessment indices, CCI and ACCI scores have certain value in evaluating the short- and long-term prognosis of ACLF patients.