Worldwide, indigenous peoples display a high burden of disease, expressed by profound health inequalities in comparison to non-indigenous populations. This study describes mortality patterns among the Guarani in Southern and Southeastern Brazil, with a focus on health inequalities. The Guarani population structure is indicative of high birth and death rates, low median age and low life expectancy at birth. The crude mortality rate (crude MR = 5.0/1,000) was similar to the Brazilian national rate, but the under-five MR (44.5/1,000) and the infant mortality rate (29.6/1,000) were twice the corresponding MR in the South and Southeast of Brazil. The proportion of post-neonatal infant deaths was 83.3%, 2.4 times higher than general population. The proportions of ill-defined (15.8%) and preventable causes (51.6%) were high. The principal causes of death were respiratory (40.6%) and infectious and parasitic diseases (18.8%), suggesting precarious living conditions and deficient health services. There is a need for greater investment in primary care and interventions in social determinants of health in order to reduce the health inequalities.