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Introduction: World Health Organization (WHO) recommends the implementation of 'Best buys', cost-effective interventions that address risk factors of non-communicable diseases (NCDs). However, country responses to the implementation of these have been slow and undocumented. The aim of this study was to identify and understand challenges and enablers for the implementation of WHO 'Best buys' for risk factors of diabetes and hypertension in South Africa (SA)., Methods: a mixed methods research with a sequential dominant status design was used starting with a document review to take stock of WHO 'Best buys' in policy in SA. A qualitative study using key informant interviews was then done to identify and understand challenges and enablers for implementation. A triangulation approach for the analysis of both document review and qualitative data was used., Results: SA has made good progress in including the WHO 'Best buys' in the policy. However, several challenges hamper the successful implementation. Most challenges were related to upstream policy implementation processes such as competing interests of actors, lack of balance between economic vs health gains, and lack of funding. Enabling factors included multi-sectoral engagement and collaboration; community ownership and empowerment; building partnerships for co-creation of enabling environments; leveraging on the existing infrastructure of other health programs; contextualization of policies and programs; and political will and leadership., Conclusion: SA has made good progress in including WHO 'Best buys' targeting risk factors of diabetes and hypertension in policy, however, various contextual barriers influence effective implementation. Hence, there is a need to leverage enabling factors to foster the implementation of WHO 'Best buys' interventions targeting risk factors of diabetes and hypertension in South Africa., Competing Interests: There authors declare no competing interests., (Copyright: Jeannine Uwimana Nicol et al.)