INTRODUCTIONThis paper outlines the protocol, history, and scope of the Asenze Cohort Study in KwaZulu-Natal, South Africa. South Africa is a middle-income country shaped by the legacies of apartheid, periods of violent political instability, and an initial refusal of the government to acknowledge human immunodeficiency virus (HIV) as the cause of acquired immune deficiency syndrome (AIDS). These historic and ongoing challenges have led to South Africa having one of the highest prevalence rates of people living with HIV/AIDS [1] and one of the highest rates of socioeconomic inequality [2].The HIV/AIDS epidemic has increased the burden of childhood developmental disability and challenges to adolescent health and well-being in low-income and middle-income countries. HIV/AIDS is a multi-system, chronic illness whose impact on child health is physical, cognitive, and/or psychological. Children whose parent(s) are living with HIV/AIDS may be affected directly, through vertical transmission from mother to child, or indirectly, due to comorbidities or early mortality of a caregiver, which may in turn impact the quality of child care. HIV is a leading cause of disability across South Africa, including KwaZulu-Natal, the province with the highest prevalence of HIV [3]. Given HIV's im-The Asenze cohort is set in South Africa, a middle-income country impacted by one of the highest global rates of people living with HIV/AIDS and high levels of socioeconomic inequality. This longitudinal population-based cohort of children and their primary caregivers assesses household and caregiver functioning, child health, social well-being, and neuro-development from childhood through adolescence. Almost 1,600 children born at the peak of the human immunodeficiency virus epidemic (2003)(2004)(2005) were followed (with their primary caregivers) in 3 waves, between 2008 and 2021, at average ages of 5, 7, and 16. Wave 3 is currently underway, having assessed over 1,100 of the original wave 1 children. Wave 4 begins in 2022. The study, with a dyadic structure, uses a broad range of measures, validated in South Africa or recommended for global use, that address physical, social and neuro-development in childhood and adolescence, and the social, health, and psychological status of children's primary caregivers. The Asenze study deepens our understanding of childhood physical, cognitive, and social abilities and/or disabilities, including risk-taking behaviors, and biological, environmental, and social determinants of health. We anticipate the findings will contribute to the development of community-informed interventions to promote well-being in this South African population and elsewhere.