Background and aims Hepatitis B related acute-on-chronic liver failure (HBV-ACLF) has a poor prognosis with very high mortality.Experience in nucleoside analogues treated patients with HBV-ACLF is limited.This study aimed to evaluate the efficacy and safety of Entecavir, Lamivudine and Telbivudine in treating patients with HBV-ACLF and to validate TPPM model in these patients.Methods In this retrospective study, we enrolled 283 patients with HBV-ACLF (100 treated with Entecavir, 98 treated with Lamivudine and 85 treated with Telbivudine).There were no significant differences in baseline clinical and virological characteristics between patients treated with Entecavir, Telbivudine or Lamivudine.Results There were no significant differences in the 4 and 12-week survival rates of Entecavir, Telbivudine and Lamivudine-treated patients (79.00%, 81.18%, and 86.73%, respectively at 4 weeks and 67.00%, 65.88%, and 73.47%, respectively at 12 weeks).Patients in all three groups achieved an improvement of MELD score.Using the Hosmor and Lemeshow test, the validation of TPPM for HBV-ACLF demonstrated a good degree of fit with disease prognosis.Based on this unique group of patients, the TPPM with an AUC of 0.787 was superior to MELD which had an AUC of 0.736 in the prediction of 12-weeks mortality.TPPM had an AUC of 0.733 and MELD had an AUC of 0.672 in the prediction of 4-weeks mortality.Using a cutoff of 0.22 for 12-weeks mortality prediction by TPPM, the positive predictive value was 49.66%, with a negative predictive value of 89.55%.Conclusion Nucleotide analogs including Entecavir, Lamivudine and Telbivudine treatment prevented disease progression and increased the survival of patients with HBV-ACLF.Validation of the established TPPM scoring system in this study confirmed its superior predictive value for HBV-ACLF patients when compared with MELD.