In 2018, ~10 million individuals developed TB disease globally, of which ~1.5 million died; HIV was the leading cause of death. Ongoing transmission results from an estimated 4.3 million “missing” TB cases along with active TB cases not retained in care. We will conduct our study in South Africa (TB prevalence=852/100,000 population; HIV co-infection=>50%), where a recent TB cascade analysis and national TB program indicators report significant gaps along the entire TB care cascade. Qualitative studies suggest TB stigma as a barrier to case finding, care seeking, treatment initiation, and adherence. However, few studies have quantified the impact of stigma on the TB care cascade, fewer have used validated stigma measures, and none have employed prospective, full care cascade study designs. We propose a 4-aim, rigorous, multilevel, mixed-methods study. We will perform household surveys, which will be aggregated into community-level data and incorporated into the analysis of all aims. Aim 1: Utilize mixed-methods to identify and measure individual- and community-level stigma and social determinants associated with presentation for TB testing among actively referred contacts. We will conduct a prospective study amongst symptomatic HHCs actively referred for testing (n= 750) to investigate the relationships within and between the multiple levels of TB and HIV stigma and other social determinants and uptake of TB testing. Aim 2: Utilize mixed-methods to identify and measure individual- and community-level stigma and social determinants associated with returning for test results among symptomatic individuals tested for TB. We will conduct a prospective study of individuals with TB symptoms who passively present to a study clinic and are tested for TB (n= 1000) to investigate the relationships between the multiple levels of TB and HIV stigma and other social determinants and returning for or obtaining the test results. Aim 3: Utilize mixed-methods to identify and measure individual- and community-level stigma and social determinants associated with LTFU and treatment outcomes among individuals initiated on TB treatment. We will conduct a prospective study among TB patients initiating treatment (n= 1250) to investigate the association of anticipated, enacted and internalized TB and HIV stigma on LTFU and poor TB treatment outcomes. Qualitative methods will explore the trajectory, persistence, and impact of perceived and experienced TB stigma during and after treatment. Aim 4: Utilize mixed-methods to identify and measure individual- and community-level stigma and social determinants associated with LTFU from HIV care following TB treatment among co-infected individuals. Relevant data for TB/HIV co-infected participant previously collected as part of Aim 3 (n= ~600), and additional HIV outcome data will be used. Through this, we will investigate the presence and potential impact of intersecting stigmas on retention in HIV care following completion of TB treatment. This study will ultimately inform targeted, multi-level interventions, rooted in the needs and challenges of communities, theoretically informed, and fully contextualized, to address the TB crisis in South Africa, and inform similar interventions globally.