The predominantly Progressive, Indeterminate, and predominantly Regressive (P-I-R) classification extends beyond staging and provides information on dynamic changes of liver fibrosis. However, the prognostic implication of P-I-R classification is not elucidated. Therefore, in the present research, we investigated the utility of P-I-R classification in predicting the on-treatment clinical outcomes in an extension study on a randomized controlled trial which originally enrolled 1000 patients with chronic hepatitis B (CHB) and biopsy-proven histological significant fibrosis and treated them for more than 7 years with entecavir-based therapy. Among the 727 patients with a second biopsy at treatment week 72, we compared P-I-R classification and Ishak score changes in 646 patients with adequate liver sections for the histological evaluation. Progressive, Indeterminate, and Regressive cases were observed in 70%, 17%, and 13% of patients before treatments and 20%, 14%, and 64% after 72-week treatment, respectively, which could further differentiate the histological outcomes of patients with stable Ishak scores. The 7-year cumulative incidence of hepatocellular carcinoma (HCC) was 1.5% for the Regressive cases, 4.3% for the Indeterminate cases, and 22.8% for the Progressive cases (p<0.001). After adjusting for age, treatment regimen, platelet counts, cirrhosis, Ishak fibrosis score changes and Laennec staging, the post-treatment Progressive had a hazard ratio of 17.77 (vs. post-treatment Regressive; 95% CI: 5.55-56.88) for the incidence of liver related events (decompensation, HCC, death/liver transplantation).The P-I-R classification can be a meaningful complementary to the Ishak fibrosis score not only in evaluating the histological changes but also in predicting the clinical outcomes.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.