OBJECTIVE: This retrospective study evaluated the therapeutic effects of entecavir (ETV) versus tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients with high viral loads. METHODS: A total of 120 high-viral-load CHB patients were enrolled and assigned to two treatment groups: the ETV group (n = 56) and the TDF group (n = 64). Comparative assessments included hepatitis B virus deoxyribonucleic acid (HBV-DNA) levels, hepatitis B e antigen (HBeAg) seroconversion rates, alanine aminotransferase (ALT) normalization, clinical efficacy, safety, biological and virological responses, biochemical indicators, and treatment satisfaction. RESULTS: The TDF group showed significantly higher HBV-DNA and HBeAg seroconversion rates, as well as ALT normalization, compared to the ETV group at both 24 and 48 weeks post-treatment (all P <
0.05). Additionally, the TDF group demonstrated better clinical efficacy (P <
0.05). While demonstrating no significant difference in the incidence of adverse reactions compared to the ETV group (P >
0.05). Significantly higher biological and virological response rates, as well as treatment satisfaction, were also observed in the TDF group (all P <
0.05). Furthermore, the TDF group exhibited superior efficacy for reducing abnormal biochemical markers (P <
0.05). CONCLUSIONS: These findings suggest that TDF is more effective than ETV for treating high-viral-load CHB patients.