AbstractDespite significant advances in the treatment and care of people with HIV (PWH), several challenges remain in our understanding of disease pathogenesis to improve patient care. HIV infection can modify the host epigenome and as such can impact disease progression, as well as the molecular processes driving non-AIDS comorbidities in PWH. Epigenetic epidemiologic studies including epigenome-wide association studies (EWAS) offer a unique set of tools to expand our understanding of HIV disease and to identify novel strategies applicable to treatment and diagnosis in this patient population. In this review, we summarize the current state of knowledge from epigenetic epidemiologic studies of PWH, identify the main challenges of this approach, and highlight future directions for the field. Emerging epigenetic epidemiologic studies of PWH can expand our understanding of HIV infection and health outcomes, improve scientific validity through collaboration and replication, and increase the coverage of diverse populations affected by the global HIV pandemic. Through this review, we hope to highlight the potential of EWAS as a tool for HIV research and to engage more investigators to explore its application to important research questions.