OBJECTIVE: To conduct a multicenter randomized controlled trial of the efficacy of standardized Chinese herbal medicines (CHMs) against acuteon-chronic liver failure (ACLF) and provide reproducible and high-level evidence for clinical practice.METHODS: This is a prospective,multicenter,centrally randomized controlled trial.Patients diagnosed with hepatitis B virus-related ACLF (n =510) will be allocated to the standard medical therapy or CHM group at a 1 ∶ 1 ratio.Two CHMs will be used on the basis of the traditional Chinese medicine syndrome: Liangxue Jiedu granules for excess syndromes and Yiqi Jiedu granules for deficiency syndromes.The primary outcome is transplant-free survival at week 12.The secondary outcomes are (a) transplant-free survival at week 24,(b) liver function as assessed using the model for end-stage liver disease score at week 12,(c) liver function as assessed using the Child-Pugh score at week 12,and (d) the incidence of complications at week 12.DISCUSSION: The effectiveness and safety of CHM formulations will be assessed following treatment for ACLF.