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In South Africa, adolescent girls and young women (AGYW) are at risk of poor mental health, HIV infection and early pregnancy. Poor mental health in AGYW is associated with increased sexual risk behaviours, and impeded HIV testing and care. Using in-depth interviews and focus group discussions, we explored subjective experiences of mental health and sexual and reproductive health (SRH) amongst 237 AGYW aged 15–24 years in five South African districts. Respondents shared narratives of stress, emotional isolation, feelings of depression, and suicidal ideation, interconnected with HIV, pregnancy and violence in relationships. Findings show that AGYW in South Africa face a range of mental health stressors and lack sufficient support, which intersect with SRH challenges to heighten their vulnerability. Framed within the syndemic theory, our findings suggest that South African AGYW’s vulnerability …