The Southern United States remains disproportionately burdened by HIV, with persistently high diagnosis rates, elevated community viral loads, and severe disparities in clinical trial participation among minority populations. This comparative study analyzes case studies from five Southern metropolitan statistical areas alongside literature on structural inequities and clinical research exclusion. Findings reveal that despite community strengths—such as faith-based institutions and dedicated local healthcare providers—systemic barriers, including outdated federal funding formulas, policy inertia, and persistent medical mistrust, undermine HIV care and research equity in the region. Elevated community viral load levels in segregated and rural Southern communities correlate with healthcare inaccessibility, poverty concentration, and stigma. Additionally, Southern minority populations are grossly underrepresented in HIV clinical trials, with participation rates falling far below their epidemiological burden. This exclusion jeopardizes both the scientific validity of research outcomes and equitable access to emerging biomedical interventions. The study recommends realigning federal resource allocation, expanding decentralized care and research infrastructures, integrating culturally competent recruitment strategies, and leveraging community-based participatory research models. Without regionally tailored interventions that address the structural and sociocultural realities of the South, national efforts to end the HIV epidemic will continue to falter.