In the USA, Black women are at disproportionately higher risk for HIV compared to women of other races/ethnicities, which can be explained by the Substance Abuse, Violence and AIDS (SAVA) syndemic. Disparities in HIV, substance use and violence are driven by multiple influences, including structural factors (e.g. housing and poverty), which exacerbate social- and individual-level factors leading to more sex partners, engaging in unprotected sex, having sex for money, experiencing forced sex from an intimate partner or increased substance use, all of which increase HIV risk. Pre-exposure prophylaxis (PrEP), a pill that can prevent HIV, is a discreet and underutilised method that Black women experiencing syndemics can use to decrease their risk. This study explored Black women's interest in, and barriers to adopting PrEP over 6 months. Thirty Black women (age M = 32.2) who experienced multiple substance use, violence and HIV-related syndemic factors were interviewed four times over a 6-month period. Results demonstrated that experiencing intimate partner violence, substance use, community violence and other structural factors (poor access to social services, transport and childcare) all acted as barriers to PrEP adoption. Future research should consider multi-level interventions that include methods such as media campaigns, providing PrEP or referrals where women who experience syndemic and structural factors seek help, and implement a PrEP adherence programmes and interventions in support group settings.