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Background: High hepatitis B surface antigen (HBsAg) level predicts hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients with low viral load. The role of longitudinal HBsAg levels in predicting HCC in HBeAg-positive CHB patients remains unknown., Method: HBeAg-positive CHB participants from the REVEAL-HBV cohort with ≥2 HBsAg measurements before HBeAg seroclearance were enrolled. Group-based trajectory modelling identified distinct HBsAg trajectory groups during a median of 11 years of HBeAg-positive status. Cox regression models were applied for investigating independent predictors of HCC and estimating adjusted hazard ratio (HR adj ) with a 95% confidence interval (CI). A p-value less than 0.05 was considered statistically significant., Results: A total of 319 patients were enrolled and classified by HBsAg trajectory patterns as (A) persistently high group (n = 72): HBsAg persistently ≥10 4  IU/mL, and (B) non-stationary group (n = 233): low HBsAg at baseline or declining to <10 4  IU/mL during the follow-up. Group B had higher proportions of abnormal ALT levels, HBV genotype C and basal core mutation than group A (p < 0.05); age at entry and gender were comparable. The annual incidence of HCC in group A and group B were 0.37% and 1.16%, respectively (p = 0.03). In multivariate analysis, age >40 years (HR adj [95% CI] = 4.11 [2.26-7.48]), genotype C (HR adj [95% CI] = 4.39 [1.96-9.81]) and the non-stationary group (HR adj [95% CI] = 3.50 [1.49-8.21]) were independent predictors of HCC. Basal core promoter mutation was the only risk factor of HCC in the persistently high HBsAg group (HR adj [95% CI] = 32.75 [5.41-198.42])., Conclusion: Patients with persistently high HBsAg levels during HBeAg-seropositive stage represent a unique population with low risk of HCC development., (© 2024 John Wiley & Sons Ltd.)