Southern Africa is the epicenter of the HIV and tuberculosis (TB) epidemic, and South Africa is at the center of the COVID-19 pandemic in Africa. There is an urgent need for robust epidemiology and implementation science to address the interacting burdens of HIV, TB, and other (emerging) coinfections and non-communicable diseases (NCDs). The International epidemiology Databases to Evaluate AIDS in Southern Africa (IeDEA-SA) has defined six specific aims for the fourth funding period (IeDEA-SA IV): (1) to study outcomes along the continuum of HIV care in adults; (2) to study outcomes in pregnant women, infants, children, and adolescents; (3) to study NCDs, hepatitis B and sexually transmitted infections (STIs); (4) to study the clinical and public health epidemiology of TB; (5) to study cancer prevention, burden, and care; and (6) to study mental health and substance use disorders. Further, we defined six cross-cutting themes: (i) the impact of the COVID-19 pandemic on health services; (ii) gender equity; (iii) capacity building; (iv) digital transformation; (v) open science; and (vi) the United Nations Sustainable Development Goals, which we will develop and prioritize within each aim. Innovations include the addition of the Western Cape Provincial Health Data Centre (WC PHDC), the South African HIV Cancer Match study, the establishment of pre-Exposure prophylaxis cohorts, and the evaluation of novel technologies (for example, a point-of-care genome-sequencing device, a hand-held colposcopic device for cervical cancer screening, or tools to study the transmission of TB in the health care setting) and novel statistical and mathematical modeling approaches. Multiregional Sentinel Research Networks (NCD-Sentinel Research Network [SRN], TB-SRN, Adolescent and Young Adult Network of IeDEA) on NCDs, TB, and adolescents and youth will harmonize data collection across the six IeDEA regions in low- and middle-income countries. The Fogarty-IeDEA Mentorship Program will strengthen capacity building among early-stage investigators. IeDEA-SA now follows nearly 1.3 million people living with HIV, including 285,000 individuals from the private sector (the Aid for AIDS program AfA), and 370,000 with ART duration > ten years. IeDEA IV will add data from 600,000 HIV-negative people through AfA and information from up to 4 million HIV-negative individuals from the WC PHDC in specific analyses. Within IeDEA, the Southern African region includes by far the largest number of adults and children. The COVID-19 pandemic now highlights the importance of epidemiologic research and implementation science across the health system. IeDEA-SA is well- placed to address the specific aims and cross-cutting themes outlined in this application, through its successful track-record of collaboration between the scientific and operational leadership at the Universities of Bern and Cape Town, partnership with several African universities (including the Kwazulu-Natal Research Innovation and Sequencing Platform), United States and European universities, and with the World Health Organization and the Joint United Nations Programme on HIV/AIDS.