The significance of hepatitis B e‐antigen (HBeAg) seroclearance (ESC) in the long term is not well defined. The current study aimed to determine the clinical outcomes, the factors and predictive scores for hepatocellular carcinoma (HCC), and hepatitis B surface antigen (HBsAg) seroclearance of a large cohort of patients undergoing ESC. Patients with documented ESC were followed up 3‐ to 6‐monthly. Baseline characteristics and longitudinal laboratory results were recorded. Predictive scores for HCC (HCC‐ESC) and HBsAg seroclearance (HBsAg‐ESC) were derived from multivariate Cox regression models. A total of 723 patients underwent ESC with a median ESC age and follow‐up of 36.0 and 18.3 years, respectively. Only 3.5% and 3.0% had persistently normal alanine aminotransferase (ALT) and HBV DNA <2logs IU/mL, respectively, after ESC. For patients with 100%, 100%‐90%, 90%‐50%, 50%‐10%, 10%‐0%, and 0% normal ALT after HBeAg seroclearance, the rate of HCC was 4.3%, 2.2%, 3.6%, 3.9%, 17.3%, and 37.2% at 20 years after ESC, respectively (P < 0.001). At 20 years after ESC, the cumulative incidence of HCC and HBsAg seroclearance was 7.9% and 13.5%, respectively, with an overall survival of 91.5%. ESC age, male sex, cirrhosis, hypoalbuminemia, viral load, and ALT were significant factors for HCC, whereas ESC age, male sex, viral load, and antiviral therapy were significant factors for HBsAg seroclearance. The area under receiver operating characteristics for HCC‐ESC and HBsAg‐ESC scores to predict HCC and HBsAg seroclearance at 20 years after ESC was 0.92 and 0.74, respectively. Conclusion: Male sex, older age at ESC, ALT, and higher level of HBV DNA were associated with higher rates of HCC after ESC. HCC‐ESC and HBsAg‐ESC predictive scores can determine the likelihood of developing HCC and achieving HBsAg seroclearance. (Hepatology 2018)