IntroductionHealth-related quality of life (HRQoL) data are necessary for conducting cost-utility analyses (CUAs) as part of health technology assessments (HTAs), but the lack of robust HRQoL data may delay or even prevent patient access to medicines when National Health Insurance is introduced in South Africa. This study aimed to make recommendations for evidence generation activities to support national HTA in the public health sector, with a focus on creating South African HRQoL data suitable for CUAs.MethodsA systematic review of HRQoL research in South Africa formed the basis for three analyses. The first analysis quantified and evaluated the suitability of HRQoL studies for CUAs. The second analysis determined the performance indicators of the research output and identified collaborative networks through bibliometric analyses. The third analysis critiqued the translation methodology of the HRQoL instruments retrieved in the systematic review.ResultsBased on the published literature, existing HRQoL data are unlikely to support CUAs because they were derived from observational or cross-sectional studies that lacked the methodological details necessary to determine their scientific merit according to HTA requirements. Overall, there was a lack of research continuity in this field, with numerous isolated research networks. Despite the strong contribution of South African based researchers and organizations in this area, their performance was below that of international counterparts. Since only a few HRQoL instruments suitable for CUAs would be valid in the South African context, HRQoL research output in South Africa could be optimized by using more rigorous study designs and by the expansion of researcher networks to include those working in HTA and related fields. The three-level EQ-5D is the tool best suited for use in South Africa, so its utilization should be encouraged and supported by establishing a South African value set.ConclusionsFuture data generation activities should incorporate the recommendations from this study because existing South African HRQoL data are likely to be inadequate for conducting CUAs in national HTA.