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Background: A multi-sectoral response is advocated by international organisations as a good strategy to address the multiple drivers and impact of human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), and was historically mandated as a condition of funding. In March 2017, the South African National AIDS Council (SANAC) launched the latest 5 year National Strategic Plan (NSP) to address HIV, sexually transmitted infections and tuberculosis. As with previous iterations, the NSP calls for multi-sectoral action (MSA) and mandates AIDS councils (ACs) at different levels to coordinate its implementation. Efforts have been made to advocate for the adoption of MSA in South Africa, yet evaluation of these efforts is currently limited. Objective: This paper assesses the implementation of a multi-sectoral response to HIV in South Africa, through a case study of the Mpumalanga Province. Methods: We identified and reviewed key policy documents, conducted 12 interviews and held six focus group discussions. We also drew on our involvement, through participant observation, in the development of NSPs and in AC meetings. Results: SANAC is struggling to provide much-needed support to provincial, district and local ACs. Therefore, most ACs are generally weak and failing to implement MSA. Membership is voluntary, there is a lack of sustained commitment and they do not include representatives from all sectors. There is little capacity to undertake the activities necessary for coordinating the implementation of MSA, and unclear roles and responsibilities within ACs result in divisions and tension between sectors. There is inadequate senior political leadership and funding to facilitate effective implementation of MSA. Conclusion: We identified three interventions that we argue are required to support the effective implementation of MSA: strengthening and stabilising the SANAC structure; building capacity of ACs; and creating an enabling environment for effective implementation of MSA through political leadership, support and resourcing of the HIV response. [ABSTRACT FROM PUBLISHER]