Abstract: OBJECTIVE To observe the high risk factors for acute on chronic liver failure (ACLF) in patients with chronic hepatitis B virus (HBV) infection and analyze the values of three prognostic scoring models. METHODS Totally 100 chronic HBV infection patients complicated with ACLF who were treated in Wenzhou Hospital of Traditional Chinese Medicine were assigned as the study group, meanwhile, 100 patients with chronic HBV infection were set as the control group. The clinical data were compared between the two groups, the influencing factors were analyzed, and the receiver operating characteristic (ROC) curve analysis was performed for the values of model for end stage liver disease (MELD), MELD-Na and iMELD scores in assessment of prognosis. RESULTS There were significant differences in history of drinking, history of medication (antiviral drugs, hepatotoxic drugs), history of surgery, prevalence of viral overlap infection, bacterial infection and high PCR-HBV DNA quantification between the study group and the control group (P<0.05). Multivariate logistic analysis showed that the history of drinking, hepatotoxic drugs, history of surgery, viral overlap infection, bacterial infection and high PCR-HBV DNA quantification were the independent high risk factors for ACLF in the patients with chronic HBV infection (P<0.05), and the antiviral drug was the independent protective factor (P＜0.05). The MELD, iMELD and MELD-Na scores of the survival group were significantly lower than those of the death group (P<0.05). The sensitivity of MELD was 62.3% in assessment of prognosis, iMELD 67.4%, MELD-Na 65.4%; the specificity of MELD was 86.4% in assessment of prognosis, iMELD 80.8%, MELD-Na 83.6%. CONCLUSION The high risk factors for ACLF in the patients with chronic HBV infection include the history of drinking, hepatotoxic drugs, history of surgery, viral overlap infection, bacterial infection and high PCR-HBV DNA quantification. It is necessary for the hospital to take targeted and effective prevention countermeasures. The MELD, iMELD and MELD-Na scoring models have high values in assessment of the prognosis.