South Africa remains the epicenter of the Human Immunodeficiency Virus (HIV) epidemic, with close to 8 million South Africans estimated to be HIV positive (2021 statistics). South Africa also has the largest antiretroviral therapy (ART) program worldwide, with 62% of HIV infected adults receiving ART in 2017.(UNAIDS Data, 2017). The risk of cancer is markedly increased in people living with HIV (PLHIV) - in particular, certain High-grade B cell lymphomas are over-represented within this group. This increased risk persists even in the ART era. In resourced-constrained settings, patients with HIV-associated lymphomas typically present with advanced staged disease, have unusual clinical presentations, and challenging to treat. In addition to abnormal immune function which leads to chronic inflammation and immune exhaustion, PLHIV display distinct pathobiological entities including immune-phenotype, genetic/molecular alterations, and virus-driven oncogenesis. Further insight is required regarding the biology and pathogenesis of lymphoma that occurs in HIV/AIDS patients. This area of research is of critical need in South Africa, and this talk will provide an overview of the lymphoma research at the University of Cape Town aimed to develop knowledge and tools which will allow for improved pathways to disease diagnosis, identification of novel diagnostic markers of lymphoma, and the development of innovative diagnostic and therapeutic approaches for patients.