Welfare states, in general, aim to mitigate social inequalities; however, in differentiating rights among social groups, their institutional architecture may further deepen pre-existing disparities. In the field of healthcare, this phenomenon has been coined as healthcare system segmentation; that is, the co-existence of different and independent healthcare arrangements, each of them targeting distinct social groups. Particularly prevalent in the Global South, healthcare system segmentation is largely neglected by the scholarship, and the few existing studies focus on contemporary manifestations of the phenomenon, while its origin, evolution, and reasons for existence remain unexplored. To fill this gap, the project (HESS) aims at investigating the emergence and development of healthcare system segmentation in twelve South American countries from a comparative and historical perspective. First, it will describe and analyse healthcare system segmentation’s (a) emergence and expansion, (b) inclusion and exclusion of social groups, (c) cross-country variation, and (d) temporal distribution. Second, it will explain whether the extent of segmentation observed within and across countries can be explained by economic, political, social, and/or policy-field specific factors. To do so, HESS will construct a novel dataset on the historical development of healthcare system segmentation in the region. This data will be made publicly available on a newly developed website, fostering further research in the domain. Adopting document analysis, descriptive statistics, and qualitative comparative analysis (QCA), the project will enrich theoretical and empirical understandings of welfare states and healthcare systems of the Global South, as well as provide guidance for policy-making, especially in light of the increasing global call for Universal Health Coverage put forth by the Sustainable Development Goals and most recently by the COVID-19 pandemic.