Background: Preventing hepatocellular carcinoma (HCC) is a major concern of antiviral therapy in chronic hepatitis B. There are conflicting reports about the effects of entecavir (ETV) and tenofovir disoproxil fumarate (TDF) on HCC prevention. Here, we assessed these two antivirals on prevention of HCC. Methods: A retrospective cohort study was conducted using Korean Health Insurance Review and Assessment Service database. We included treatment-naive 55 488 adults who started ETV or TDF between 2013 and 2017. The ETV and TDF groups were 1:2 matched on the basis of age, sex, comorbidities, hospital type, and year of the index date. Patients were followed until December 2018. The outcome was the development of HCC. Findings: The matched participants (18496 in the ETV and 36992 in the TDF group) was followed for a mean of 41·2 months. The incidence of HCC was not significantly different between the ETV (1·46 per 100 patient-years [PY]) and the TDF group (1·36 per 100 PY) (hazard ratio, 0·93; 99% confidence interval [CI], 0·84 to 1·03). Interpretation: In this study, we could not find ETV treatment resulted in a higher rate of HCC than TDF among patients with chronic hepatitis B. Funding Statement: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interests: The authors stated: None exist. Ethics Approval Statement: The HIRA provide the claims data with concealed individual identification of patients. This study was approved by the Institutional Review Board of HIRA (approval number: B2019-025). Informed consent from patients was waived by the Board.