The disproportionate burden of HIV-related inequities borne by African Americans in the US South amplifies the role of social determinants of health (SDH) in shaping social patterning of illness. Despite some attention, SDH remain overlooked in a biomedically oriented, federal HIV policy. Mississippi is the poorest state with the worst HIV outcomes, nationally. Using qualitative methods, we investigated how primarily African American, HIV-positive Mississippians experienced SDH and health inequities in their daily lives. Employing grounded theory and in-depth interviews ( = 25) in an urban and rural site in 2015 yielded these findings: (1) absence of an enabling structural environment; (a) HIV-stigma constructed via social discourse; (b) lack of psycho-social support and HIV education; (c) insufficient economic and social support resources; and (2) presence of family support for coping. Due to stigma, being HIV-positive seemed to lead to further status loss; diminished social position; reduced life chances; and contractions in particular freedoms. Stigma further compounded existing inequalities - contributing to the moral, social experience of those living with HIV. Trump's plan to end HIV by 2030 creates the opportunity to rethink the biomedical-paradigm and fully engage SDH - using social science theory and methods that address multi-level social determinants in ways that are also policy-responsive.