Purpose: To critically appraise and explore the underlying mechanisms of increased cancer risk in HIV with a view to revealing novel opportunities in preventing and treating cancer in HIV.Methodology:Literature search was carried out with the aid of PubMed, Google scholar and New England Journal of Medicine.Findings: Different articles were reviewed to better understand the synergistic mechanisms of oncogenesis in HIV. Although, some mechanisms are largely unclear, evidences derived from several studies clarified the oncogenic mechanisms of some factors examined in this article. Immunodeficiency appears to be pivotal and fundamental to the proneness to cancer risk in HIV whereas evidence is emerging that a direct pro-oncogenic effect of HIV, chronic immune activation (inflammation), and possible carcinogenic effects of antiretroviral drug may also contribute. Furthermore, increasing age and lifestyle behaviors such as multiple sexual partners, anal sex, intravenous drug use and alcohol use could also contribute.Unique Contribution to Theory, Practice and Policy:While the role of immunosuppression as a risk factor for malignancy in HIV is well established, other synergistic mechanisms have been in the shadows of clinical practice. This review explores novel mechanisms associated with rise in titre of inflammatory markers, direct effects of HIV tat and vpr molecules and oncogenic effects of anti-retroviral drugs.Summary:Continued research on the mechanisms of cancer risk in HIV is advocated to better understand how to intervene to mitigate cancer risk. Possible exploration and investigation of the role of tat and vpr inhibitors is recommended as tat and vpr are highly implicated in the direct oncogenic effects of HIV.