Summary – KZN-CTU The KwaZulu-Natal Clinical Trials Unit (KZN-CTU), strategically located in the epicentre of one of the world’s most severe HIV and tuberculosis epidemics, seamlessly combines the Clinical Research Sites (CRSs) of existing, high-performing CTUs at CAPRISA and the South African Medical Research Council (SAMRC). In the current funding cycle, the combined CTUs enrolled 4,713 participants in 28 protocols, with an overall retention rate of 93%. Further, several KZN-CTU scientists participated at the highest levels in the Clinical Trial Networks (CTNs), making influential new scientific contributions, including as network Protocol Chairs, that have impacted global policy/practice, including tenofovir-containing PrEP for HIV prevention, co-treatment strategies to reduce HIV-tuberculosis deaths and nevirapine prophylaxis to reduce breastfeeding transmission. This renewal application’s goal is to make even greater contributions to the scientific priorities of all 4 CTNs through novel research concepts, innovative prevention technologies (eg. CAPRISA 256 antibody) and high-quality clinical trials in high priority populations by experienced research teams at well-equipped CRSs. The KZN-CTU, led by Quarraisha Abdool Karim of CAPRISA, comprises 4 components: i) Leadership and governance, ii) Coordination and monitoring, and iii) 8 CRSs, supported by iv) 8 research support cores. The Leadership and governance component will ensure effective CTU decision-making and governance, active engagement with each CTN and oversee the efficient functioning of the CTU. The Coordination and monitoring component is responsible for coordination of clinical trial implementation at high quality. The 8 CRSs, with HIV incidence rates ranging from 4.6 to 8.2 per 100 person-years in recent trials, are in the highest burden districts of South Africa with diverse populations suited to HIV prevention, vaccine and treatment trials as well as trials in children, adolescents and pregnant