Summary: Background: Many patients with chronic hepatitis B (CHB) do not meet the definitions of the traditional natural phases and are classified as being in the grey zone (GZ). Aims: To investigate liver histology, and to establish a management strategy for patients with CHB in the GZ. Methods: This study included 1043 patients with CHB who underwent liver biopsy. Phases of natural history were determined according to the AASLD 2018 hepatitis B guidance. CHB patients in the GZ were divided into HBeAg‐positive, normal ALT and HBV DNA ≤106 IU/ml (GZ‐A); HBeAg‐positive, elevated ALT and HBV DNA ≤2 × 104 IU/ml (GZ‐B); HBeAg‐negative, normal ALT and HBV DNA ≥2 × 103 IU/ml (GZ‐C) and HBeAg‐negative, elevated ALT and HBV DNA ≤2 × 103 IU/ml (GZ‐D). Significant histological disease was defined as liver inflammation ≥G2 and/or liver fibrosis ≥S2. Results: Two hundred and forty two (23.2%) patients were in the GZ. Approximately 72.7% had significant histological disease. HBeAg‐positive GZ CHB patients had a higher proportion of significant histological disease than HBeAg‐negative GZ patients (91.1% vs. 68.5%, p = 0.002). GZ‐D (42.6%) was the dominant category, followed by GZ‐C (38.8%), GZ‐A (10.3%) and GZ‐B (8.3%). The highest proportion of significant histological disease was observed patients in GZ‐B (100.0%), followed by GZ‐A (84.0%), GZ‐D (69.9%) and GZ‐C (67.0%). Prothrombin time (PT) was an independent risk factor of significant histological disease in the HBeAg‐negative GZ. Conclusions: Over 70% of GZ CHB patients had significant histological disease. We recommend antiviral treatment for HBeAg‐positive and HBeAg‐negative GZ CHB patients with high PT. [ABSTRACT FROM AUTHOR]