Patients with chronic hepatitis B are at increased risk of hepatocellular carcinoma (HCC), while the inhibition of viral replication can represent a reasonable target for HCC prevention. Interferon-α therapy results in decreased HCC risk, which is more evident in patients with high baseline HCC risk. The majority of chronic hepatitis B patients are treated with a nucleos(t)ide analogue (NA) for several reasons including the non-sustained response after interferon-α. The effect of the first licensed and low genetic barrier NA, lamivudine, on HCC incidence, has been repeatedly evaluated. Lamivudine, compared to no treatment, reduces the HCC incidence, which may increase again in cases with lamivudine resistance. Emerging data with the currently first-line NAs, entecavir and tenofovir, suggest that they also reduce the HCC incidence. The treatment benefit in reduction of the HCC incidence is always greater in patients with high baseline HCC risk, particularly cirrhotics, and without virological remission under entecavir/tenofovir. However, the HCC risk is not eliminated even in the vast majority of patients who remain in virological remission under entecavir/tenofovir. Therefore, patients at increased baseline HCC risk should continue to undergo HCC surveillance even if they have achieved complete long-term inhibition of viral replication and improvements in liver histology.