Objective To investigate the effect of entecavir( ETV) alone or combined with interferon( IFN) on the risk of hepatocellular carcinoma( HCC) in patients with chronic hepatitis B( CHB). Methods A retrospective analysis was performed for 409 patients with CHB who were admitted to Beijing Ditan Hospital from January 2008 to December 2014,and according to their antiviral therapy,they were divided into ETV + IFN group with 169 patients( IFN treatment for ≥6 months) and ETV group with 240 patients( ETV treatment for ≥12 months). The patients were followed up to June 2019,and the development of HCC was the outcome event. The Mann-Whitney U test was used for comparison of continuous variables between two groups,and the chi-square test was used for comparison of categorical variables between two groups. The propensity score matching( PSM) method was used to eliminate baseline differences between groups,the Kaplan-Meier method and the log-rank test were used to compare the incidence rate of HCC between groups,and the Cox proportional-hazards regression model analysis was used to investigate the risk factors for the development of HCC. Results The median follow-up time in this study was 5. 4 years( IQR: 4. 9-7. 9). There was no significant difference in the cumulative incidence rate of HCC between the two groups before and after PSM( before PSM: 1. 2% vs 2. 8%,χ2= 1. 423,P = 0. 233; after PSM: 1. 7% vs 4. 1%,χ2= 1. 676,P = 0. 195),and the subgroup analysis also showed no significant difference in the cumulative incidence rate of HCC between the two groups in the non-high risk population( 1. 3% vs 1. 5%,χ2= 0. 335,P = 0. 563). The Cox proportional-hazards regression model showed that age was an independent risk factor for HCC( hazard ratio = 1. 107,95% confidence interval: 1. 005-1. 219,P = 0. 038). Conclusion For CHB patients without a high risk of cancer,compared with ETV monotherapy,ETV combined with IFN for at least 6 months does not significantly reduce the risk of HCC.