Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are first-line agents for the treatment of chronic hepatitis B (CHB). Recent studies have challenged the assumption that these agents are equally effective at preventing hepatocellular carcinoma (HCC). We aimed to determine whether the risk of HCC and mortality differ in patients with CHB treated with ETV and TDF.We performed a retrospective cohort study of Veterans Affairs patients with CHB in the USA who initiated treatment with ETV or TDF between the dates of Food and Drug Administration approval of these medications and 1 January 2017. Multivariable Cox proportional hazards regression was used to determine the association between antiviral therapy and HCC risk as well as the risk of death or liver transplantation. Propensity score adjustment and competing risks analysis were performed.We identified 2193 ETV-treated and 1094 TDF-treated patients who were followed for a mean of 5.4 years. We found no difference in the risk of HCC in ETV-treated versus TDF-treated patients (adjusted HR (aHR) 1.00, 95% CI 0.76 to 1.32). Results were similar in propensity score adjusted and competing risks analysis, and in multiple sensitivity analyses. We also found no difference in the risk of death or liver transplantation (aHR 1.16, 95% CI 0.98 to 1.39).We found no difference in the risk of HCC between patients with CHB treated with ETV versus TDF. Our results support current guideline recommendations that both agents are appropriate first-line options for the treatment of CHB.