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The aim of this study was to investigate the effects of the national HIV/AIDS control programme on district hospitals in Cameroon. A multiple case study was conducted in two district hospitals – one public and one faith-based. Data were collected by document review, semi-structured interviews and observation of managerial processes and health care delivery.Programme interventions result in a series of positive and negative effects on the functioning of district hospitals and local health systems. High input and support of staff skills were observed for antiretroviral therapy and the management of opportunistic infections. However, the impact of the programme on the stewardship function is problematic. The low implication of district management teams in the implementation of HIV/AIDS activities reduces their structural capacity to run the local health systems. Programme and health system managers failed to take advantage of opportunities to develop synergies between the HIV/AIDS programme and local health systems.The HIV/AIDS programme weakens the systemic and structural capacity of local health systems. Managers of both programmes and general health systems should analyse and adapt their interventions in order to effectively strengthen health systems. One of the research questions is to understand why health system stakeholders do not seize opportunities to develop synergies between programmes and the general system and to strengthen health systems.