The baseline alanine aminotransferase (ALT) level was reported to have prognostic value in chronic hepatitis B virus (HBV) infection, during which ALT may change over time. Instead of baseline ALT, this study aimed to study the prognostic value of the height of ALT during the course of chronic HBV infection. A total of 4376 asymptomatic hepatitis B e antigen (HBeAg) negative, surface antigen (HBsAg) carriers with baseline ALT less than 2 times the upper limit of normal (ULN) were monitored with ALT measurement and ultrasonography every 3 to 12 month for over 3 years. Maximal ALT levels during follow‐up were correlated with long‐term outcomes using morbidity and mortality data from hospital records, cancer registration, and national mortality database. Baseline ALT level was normal in 3673 subjects and increased to abnormal level in 1720 (46.8%) during a mean follow‐up period of 13.4 ± 5.2 (3.0‐28.7) years. The incidence of liver cirrhosis, hepatocellular carcinoma (HCC), and mortality increased with increasing maximal ALT level during follow‐up, especially in those with maximal ALT of at least 2 times ULN, as compared with those who maintained normal ALT. Cox regression analysis indicated that age at entry, sex, and maximal ALT level during follow‐up were significant independent factors associated with the development of cirrhosis, HCC, and mortality whereas cirrhosis was also an independent factor for HCC development and mortality. Conclusion: Persistently normal ALT was associated with excellent long‐term prognosis, whereas increasing ALT levels of at least 2 times ULN during follow‐up was associated with increasing morbidity and mortality. ALT of at least 2 times ULN is therefore an appropriate threshold for anti‐HBV therapy, whereas those with ALT 1 to 2 times ULN require liver biopsy for decision. (HEPATOLOGY 2009.)