Research has shown that transgender and nonbinary people experience health disparities. However, few studies have explored, in-depth, the health-related experiences, perceptions, needs, and priorities of transgender women of color living in the U.S. South, a region that poses unique challenges to achieving health for transgender people. This study explored the social determinants of health, healthcare experiences, and health-related priorities of transgender women of color living in the U.S. South. Using a community-based participatory research approach, we conducted iterative in-depth interviews with 15 African American/Black and Latinx transgender women in North Carolina in May-July 2019 for a total of 30 interviews. We analyzed interview data using constant comparison, an approach to grounded theory. Participants' mean age was 34 (range 19-56) years. Twenty themes emerged that were categorized into three domains: (1) social determinants of health (family rejection; bullying, discrimination, and violence; isolation; policy barriers; mistrust in systems; employment obstacles; sex work; high cost of care; transportation barriers; church antagonism; and substance misuse), (2) healthcare experiences (emotional burden of healthcare interactions; name and gender misidentification; staff discomfort and insensitivity; sexual risk assumptions; and use of nonmedical or predatory providers), and (3) health-related priorities (understanding healthcare; respect at all levels of healthcare; inclusive gender-affirming care; and comprehensive resources). Transgender women of color living in the U.S. South face profound health barriers compounded throughout the life course and have unmet healthcare needs. Participants faced multilayered minority stressors: racial discrimination from society at large and within the LGTBQ community; gender identity discrimination within their regional context and racial/ethnic communities; and exclusion from existing health equity movements for transgender women of color, which often are found in and focus on larger urban communities. Health interventions mindful of this intersection are needed, including antidiscrimination policies and increasing gender-affirming healthcare access.