Background: Fuzheng Huayu tablet is a traditional Chinese medicine (TCM) used for the treatment of liver fibrosis and cirrhosis. However, whether the combination with Fuzheng Huayu tablet could affect the antiviral efficacy of nucleos(t)ide remains a concern. The objective of this trial was to explore the impact of Fuzheng Huayu tablet on antiviral effect of entecavir in patients with hepatitis B cirrhosis. Methods: A prospective, randomized control trial was conducted. Patients with compensated hepatitis B cirrhosis were randomly divided into the treatment group (entecavir capsule plus Fuzheng Huayu tablet) and the control group (entecavir capsule plus simulant of Fuzheng Huayu), and followed up for 48 weeks. The dynamic changes of HBV DNA load, the rate of serological conversion of HBeAg, liver function, renal function and liver stiffness measurement (LSM) were monitored. The general clinical data and adverse events were also recorded. Results: There was no significant difference in the rate of virological response and cumulative virological response between the treatment group and the control group ( P > 0.05). After 48 weeks of treatment, the HBeAg seroconversion rate, biochemical response rate and LSM value were 21.05% and 4.76% ( P = 0.164), 86.96% and 65.96% ( P = 0.017), 9.5 kpa and 10.6 kpa ( P = 0.827) in the treatment group and the control group, respectively. No serious adverse events related to the study therapy occurred during the trial. Conclusions: The antiviral entecavir combined with Fuzheng Huayu tablet did not affect the antiviral effi-cacy of entecavir, but could improve the rate of biochemical response, and had a tendency to improve the rate of serological conversion of HBeAg and liver fibrosis in patients with hepatitis B cirrhosis. Fuzheng Huayu tablet is clinically safe for patients with hepatitis B cirrhosis. (c) 2022 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.