Abstract One year of treatment with entecavir (0.5 mg daily) in nucleoside-naive patients with hepatitis B e antigen (HBeAg)-positive or HBeAg-negative chronic hepatitis B (CHB) resulted in significantly improved liver histology and virological and biochemical endpoints in comparison with lamivudine. Patients who received at least 3 years of cumulative entecavir therapy in phase 3 studies and a long-term rollover study and underwent long-term liver biopsy were evaluated for improvements in histological appearance. Sixty-nine patients [50 HBeAg-positive and 19 HBeAg-negative] receiving entecavir therapy underwent long-term liver biopsy (median time of biopsy = 6 years, range = 3-7 years). Histological improvement was analyzed for 57 patients who had adequate baseline biopsy samples, baseline Knodell necroinflammatory scores ≥2, and adequate long-term biopsy samples. At the time of long-term biopsy, all patients in the cohort had a hepatitis B virus DNA level <300 copies/mL, and 86% had a normalized alanine aminotransferase level. Histological improvement (≥2-point decrease in the Knodell necroinflammatory score and no worsening of the Knodell fibrosis score) was observed in 96% of patients, and a ≥1-point improvement in the Ishak fibrosis score was found in 88% of patients, including all 10 patients with advanced fibrosis or cirrhosis at the phase 3 baseline. Conclusion: The majority of nucleoside-naive patients with CHB who were treated with entecavir in this long-term cohort achieved substantial histological improvement and regression of fibrosis or cirrhosis.