To address ongoing HIV transmission in the Rakai region of Uganda, the PEPFAR program in which the open, populations-based Rakai Community Cohort Study (RCCS) is nested recently began implementing additional combination HIV prevention (CHP) interventions: (i) Pre-Exposure Prophylaxis (PrEP); (ii) assisted Partner Notification; and (iii) Same-day antiretroviral therapy (ART). This environment provides a unique opportunity to address the following important questions: (1) To what extent do hard-to-reach populations bias HIV coverage and incidence estimates? (2) Why do some individuals continue to acquire HIV and from whom? (3) Given hard-to-reach populations, can state-of-the-art CHP in a programmatic setting reduce HIV incidence to the levels needed for HIV elimination? Our setting and research infrastructure strongly position us to answer these highly significant questions and inform current and future HIV prevention trials, evaluations, and programs. To our knowledge, no prior HIV population-based studies have empirically determined the potential effects of participation bias on HIV epidemiology and incidence due to non-inclusion of hard-to-reach populations. This study will uniquely address questions on hard-to-reach populations which are critical to understanding the true state of the epidemic, interpreting HIV prevention trials and cross-sectional studies, and informing prospects and pathways to ending the African HIV epidemic.