The Human Sciences Research Council (HSRC), in partnership with the Centers for Disease Control and Prevention (CDC), the South African Medical Research Council (SAMRC), the University of Cape Town (UCT), and the National Institute of Communicable Diseases (NICD), is conducting the sixth national HIV household survey, the 2021 South African HIV Behavioural, Sero-status and Health Survey (SABSSM VI). This milestone survey marks 20 years since the series began, when the inaugural study was commissioned by former President Nelson Mandela through the Nelson Mandela Foundation in 2001. SABSSM VI is funded by the US President’s Emergency Plan for AIDS Relief (PEPFAR) through the US CDC. The largest survey ever conducted by the HSRC, it reaches approximately 93 000 participants across all nine provinces, with around 65 000 blood specimens collected for laboratory testing.