South Africa has long recognized partnerships between the public and private sectors as a policy objective in health, but experience is still limited and poorly documented. The objectives of this article are to understand the factors that increase the likelihood of success of public-private interactions in South Africa, and identify and discuss opportunities for them to be scaled up. There is a strong legislative framework and a number of guidelines and tools that have been developed by the Treasury for managing partnerships. The review of literature confirmed the need for the state to have effective regulations in order to oversee quality and standards and to provide stewardship and oversight. The public sector requires sufficient capacity not only to manage relationships with the private sector but also to enable innovation and experimentation. Evaluation is an integral part of all interactions not only to learn from successes but also to identify any perverse incentives that may lead to unintended consequences. Four case studies show that the private for-profit sector is already engaged in a number of projects that are closely aligned to current health system reform priorities. Factors that increase the likelihood of interactions being successful include: increasing the government's capacity to manage public-private relationships; choosing public-private interactions that are strategically important to national goals; building a knowledge base on what works, where and why; moving from pilots to large scale initiatives; harnessing the contracting expertise in private providers; and encouraging innovation and learning.