OBJECTIVE: To explore the syndemic interaction between social, environmental, and structural contexts and HIV infection in peri-mining areas in South Africa. DESIGN: Mixed qualitative methods consisting of in-depth interviews (IDIs) and focus group discussions (FGDs) exploring the interaction between HIV infection and the social, environmental and structural factors affecting people living in the peri-mining areas of South Africa. Themes were analysed following the syndemic theoretical framework. SETTING: Participants were recruited from three mining companies and locations in the peri-mining communities surrounding the mining companies in Limpopo, Mpumalanga, and Northern Cape provinces. PARTICIPANTS: Inclusion criteria included mineworkers, healthcare workers, female sex workers (FSWs), injection drug users (IDUs), and other community members, ≥18 years, living in the peri-mining area at the time of participation. Three FGDs were conducted (n=30): 13 men and 17 women aged 18-55 years. IDIs were conducted with 45 participants: mineworkers (n=10), healthcare workers (n=11), FSWs (n=15), truck drivers (n=4) and IDUs (n=5). RESULTS: The findings from this study indicate that a syndemic of four socio-behavioural factors is associated with HIV acquisition in peri-mining areas. These are migrancy, accessibility to alcohol and substance use, commercial and transactional sex, and uptake of HIV prevention services. CONCLUSIONS: Our findings have implications for HIV prevention programmes in mining companies, which rely on male condom usage promotion. More emphasis on better education about HIV prevalence, transmission and up-to-date prevention alternatives, such as pre-exposure prophylaxis for mineworkers is recommended. Furthermore, collaboration with community-based organisations is recommended to wholly address the syndemic factors influencing HIV transmission in peri-mining communities.