Background: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in HBeAg-negative chronic hepatitis B (CHB). This study aimed to clarify this relationship and identify factors associated with liver histology. Patients and methods: We investigated 152 consecutive, treatment-naïve, HBeAg-negative CHB patients who had undergone liver biopsies at a tertiary medical centre in Taiwan. Clinical indications for treatment included a serum alanine aminotransferase level more than twice the upper limit of normal and an hepatitis B virus DNA level >2000 IU/ml. Factors associated with the histological indication (Ishak's grade ≥7 and/or stage ≥2) were analysed. Results: The association between the clinical and the histological indications was significant (P = 0.011). However, the agreement was poor (? value = 0.197). In patients satisfying the clinical indication, age >52 years [odds ratio (OR) = 2.669, P = 0.042], serum a-fetoprotein (AFP) level >7 ng/ml (OR = 7.070, P<0.001) and platelet count <130×109/L (OR = 11.720, P = 0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only an AFP level >7 ng/ml (OR = 10.345, P = 0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level >7 ng/ml to predict liver histology, the sensitivity and the negative predictive value could improve from 86 to 94.4% and 66.7 to 81% respectively. Conclusion: AFP level is associated with liver histology in HBeAg-negative CHB. Serum AFP level can serve as a surrogate indicator to identify patients who need antiviral treatment.