Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are now equally recommended by all international clinical guidelines as the first-line oral antiviral treatment of patients with chronic hepatitis B. Both ETV and TDF are potent nucleos(t)ide analogues with a high genetic barrier to drug resistance. The majority of patients under long-term potent nucleos(t)ide analogue treatment can achieve hepatitis B virus DNA suppression, which is associated with reduction of disease progression and development of hepatocellular carcinoma (HCC). However, in recent two years, there has been an ongoing debate on the potential differences in effectiveness of ETV and TDF on preventing HCC development. In this special issue of Hepatoma Research, we will give a thorough review on all relevant studies and meta-analyses, as well as look into the difference in methodology and statistical analyses aiming to provide a better understanding of how to interpret the findings in these observational studies and meta-analyses of observational studies.