Hepatitis D virus (HDV) infection affects more than 10 million people worldwide, with an estimated prevalence of nearly 4.5% among HBsAg-positive individuals. Epidemiological studies have shown a significant increase in the prevalence of hepatocellular carcinoma (HCC) in patients with chronic HDV infection compared to those with chronic hepatitis B virus (HBV) mono-infection. Despite the clinical findings, data on molecular oncogenic mechanisms are limited and fragmentary. Moreover, the role of HDV in promoting the development of HCC has so far been controversial, because it is difficult to weigh the respective contributions of the two viruses. In this review, we focused on the direct oncogenic action of HDV, its role in modifying the tumor microenvironment, and the genetic signature of HDV-related HCC, comparing these features with HBV-related HCC.