The peopling, origins, and early prehistory of the Americas are topics of intense debate. However, few studies have used human remains to document and interpret patterns of health and lifestyle of Paleoamericans. This study provides the first investigation to characterize oral health in a series of early Holocene skeletal remains from Lagoa Santa, Brazil, a locality containing the remains of some of the earliest inhabitants of South America (10,000–7,000 BP). The sample is composed of 949 teeth and 1925 alveoli from an estimated 113 individuals excavated from 17 archaeological sites located in the State of Minas Gerais. We compare dental caries and abscess prevalence at Lagoa Santa to a large sample of human skeletons from the Western Hemisphere Project (WHP) database using both individual and tooth/alveolus count methods. In addition, antemortem tooth loss and tooth wear were analyzed in Lagoa Santa by sex and age. The results show that Lagoa Santa dental caries and abscess prevalence are significantly higher than observed among other hunter–gatherers included in the WHP database, except when abscess prevalence is considered by individual count. Adult females have less tooth wear coupled with higher prevalence of dental caries and antemortem tooth loss than adult males. These results point to an unexpected record of poor oral health at Lagoa Santa, especially among females. A diet based on a highly cariogenic combination of wild tubers and fruits is suggested as an explanation for the elevated rate, characterizing an early adaptation to a tropical environment in South America. Am J Phys Anthropol 154:11–26, 2014. © 2014 Wiley Periodicals, Inc.