BACKGROUND: The South African Pharmacoeconomic Guidelines were published in February 2013, with the intention for application to newly approved medicines in the privates sector. However, uptake has been poor and the number of submissions negligible. OBJECTIVES: This study aims to examine the pharmacoeconomic guidelines in the context of existing legislation, policy and incentives in the private sector in South Africa to make explicit the reasons for the poor uptake and challenges to implementing the guidelines. METHODS: A review of existing legislation regulating reimbursement of medicines in the private sector was undertaken in relation to the implementation of the guidelines, as well as interviews with key stakeholders in the pharmaceutical industry, ministry of health and health insurance industries to understand attitudes to and challenges to adopting the guidelines submission criteria and results. RESULTS: Existing legislation means that results of pharmacoeconomic submissions are not enforceable – funders are not required reimburse for products should the ministry of health evaluations process deem them cost-effective. Pharmaceutical companies are thus at risk of a negative finding on reimbursement with no assurance that a positive finding will improve reimbursement for new products. As submission is currently not mandatory, this is something they will be unlikely to do. The level of strict application or flexibility within the requirements of the guidelines is also not clear. CONCLUSIONS: Uptake and engagement with the South African Pharmacoeconomic Guidelines has been poor, with no submissions formally evaluated since the guidelines were finalised. Several existing policy and legislative barriers exist which make the success of these guidelines in this current environment unlikely. Building capacity for submitting analyses as well as within the ministry of health to evaluate submissions will be critical.