OBJECTIVE: To study the prevalence of significant hepatic histopathology in chronic hepatitis B (CHB) patients with alanine aminotransferase (ALT)≤twice upper limit of normal (ULN) and its association with age, HBeAg status, hepatitis B virus (HBV)-DNA level and viral genotype. METHODS: A prospective study was conducted over a 3-year period in treatment-naive CHB patients with ALT≤twice ULN. Patients with a history of acute flare hepatitis, use of alcohol and hepatotoxic drugs, hepatitis C, hepatitis D and human immunodeficiency virus (HIV) co-infection were excluded from the study. Hepatic histopathology was assessed according to the METAVIR scoring system. RESULTS: A total of 145 patients were recruited, 81 (55.9%) of whom were male. The patients' mean age was 41.50±10.74 years (range 16-70 years). Significant hepatic inflammation was found in 59.3% of these patients, and significant hepatic fibrosis was found in 62.1%, the latter being associated with hepatitis B e antigen status, ALT levels and serum HBV-DNA, but not with their age group or viral genotype. Significant hepatic fibrosis was found in 24 of 35 CHB patients (68.6%) who were previously considered in an immunotolerance phase. CONCLUSIONS The prevalence of significant hepatic histopathology in CHB patients with serum ALT levels≤twice ULN is high. Delayed antiviral treatment can be harmful. © 2011 The Authors. Journal of Digestive Diseases © 2011 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.