Chronic hepatitis B (CHB) and liver fibrosis are high-risk factors for hepatocellular carcinoma (HCC). We assessed whether ETV plus Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine, can further reduce the risk of HCC in treatment-naïve Chinese CHB patients with Ishak fibrosis score of ≥3 points derived from our parent double-blind randomized placebo-controlled trial.After a 72-week comparison between ETV+BRC and ETV+placebo treatment, participants were eligible to enter an open-label treatment phase and were followed up every 6 months. The primary [secondary] endpoints were the incidence of HCC [liver-related deaths, non-HCC events, and non-liver-related deaths]. Modified intention-to-treat (mITT), intention-to-treat (ITT), and per-protocol (PP) populations were defined for the time-to-event analysis.A total of 1000 patients were recruited, the median age was 42.0 years, 69.9% were male, 58.3% had positive HBeAg. In the mITT population, the 7-year cumulative incidence of HCC [liver-related deaths] was 4.7% [0.2%] for ETV+BRC, which was significantly lower than 9.3% [2.2%] for ETV (p =0.008 [p =0.030]). Notably, ETV+BRC treatment yielded a lower incidence of HCC in those who did not achieve regression of fibrosis at week 72 than did ETV treatment (p =0.018). There were no differences in the other two secondary endpoints or safety profiles between the groups. Multivariable Cox proportional regression analysis including the treatment allocation as a parameter also demonstrated that ETV+BRC treatment was a protective factor for the incidence of HCC. The ITT and PP analyses showed consistent results.ETV plus BRC combination treatment could further reduce the risk of HCC and liver-related deaths in CHB patients with advanced fibrosis or cirrhosis, which may have important clinical implications for HCC prevention. Lay summary ●It is clinically important to determine how to further reduce the risk of hepatocellular carcinoma (HCC) when it is not possible to eliminate hepatitis B virus with entecavir (ETV) treatment. ●We performed a long-term extension of our 72-week parent prospective randomized placebo-controlled trial, which revealed that the Biejia-Ruangan compound (BRC), an anti-fibrotic traditional Chinese medicine (TCM), could further reduce the incidence of HCC by 51.1% and liver-related deaths by 89.9% in Chinese CHB patients receiving ETV treatment. ●Given the poor prognosis of HCC, the findings may have important clinical implications and serve as a basis for further mechanism studies of TCM to explore a more effective strategy to reduce the risk of HCC.Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.