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Early determination of the prognosis of patients with hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is important to guide clinical management and decrease mortality. The aim of this study was to develop a new simplified prognostic score to accurately predict outcomes in patients with HBV-ACLF. Prospective clinical data from 2,409 hospitalized patients with acute deterioration of HBV-related chronic liver disease were used to develop a new prognostic score that was validated in an external group. A total of 954 enrolled patients with HBV-ACLF were diagnosed based on the Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) criteria. Six predictive factors were significantly related to 28-day mortality and constituted a new prognostic score (=1.649×ln(international normalized ratio)+0.457×hepatic encephalopathy score+0.425×ln(neutrophil)+0.396×ln(total bilirubin)+0.576×ln(serum urea)+0.033×age). The C-indices of the new score for 28-/90-day mortality (0.826/0.809) were significantly higher than those of 4 other scores (COSSH-ACLF, 0.793/0.784; CLIF-C ACLF, 0.792/0.770; MELD, 0.731/0.727; MELD-Na, 0.730/0.726; all p <0.05). The prediction error rates of the new score for 28-day mortality were significantly lower than those of the 4 other scores: COSSH-ACLF (15.9%), CLIF-C ACLF (16.3%), MELD (35.3%) and MELD-Na (35.6%). The probability density function evaluation and risk stratification of the new score also showed the highest predictive values for mortality. These results were then validated in an external cohort. A new prognostic score based on 6 predictors, without an assessment of organ failure, can accurately predict short-term mortality in patients with HBV-ACLF and might be used to guide clinical management. Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome that is associated with a high short-term mortality rate. We developed a simplified prognostic score for patients suffering from this condition based on a prospective multicentre cohort. This new score had better predictive ability than 4 other commonly used scores. [Display omitted] • We developed a new prognostic COSSH-ACLF II score based on 6 predictors from a large cohort. • This score simplifies triage and can be used to stratify patients with HBV-ACLF based on their short-term mortality risk. • The new score has improved prognostic accuracy and sensitivity for patients with HBV-ACLF. • This score could be used to guide clinical management and reduce the currently unacceptable mortality rate. [ABSTRACT FROM AUTHOR]