The retrospective scrutiny of studies that were originally designed to assess the antiviral activity of interferon (IFN) and nucleos(t)ide analogues (NUC) suggested reduced incidence of hepatocellular carcinoma (HCC) in responders. The interpretation of these studies, however, is questioned by the heterogeneity of patient referral, adoption of surrogate end-points, lack of control arms and, overall, by the lack of power to capture enough hard end-points of the natural history of hepatitis B, including HCC. Another point of criticism is that above all, IFN studies could have been affected by study enrolment skewed towards patients with less advanced liver disease, who had a better predicted compliance to therapy but a lower risk of developing HCC in the short-term. In my opinion, these constraints coupled with the lack of patient stratification by HCC predictors, make the evaluation of the prophylactic activity of IFN and NUC even more difficult. Overall, while single studies provide some evidence for a reduced HCC incidence in virological responders, particularly in those with moderate liver fibrosis, we still lack confirmation that anti-HBV therapy prevents HCC in patients with an established cirrhosis, too. Finally, tertiary prevention with anti-HBV treatments is controversial, due to the existence of a few, methodologically flawed studies.