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In this study, we expand on previous discussions of the origin, evolution, and relationship of treponemal infections as they occur in the prehistoric southeastern United States. Individuals from 25 skeletal series (n = 2,410 individuals) were examined for cranial and dental lesions characteristic of treponemal infection. They lived between the Archaic period (8000\u20131000 BC) and protohistoric period (AD 1500\u20131600), and in physiographic zones from the coast to the mountains of Alabama, Florida, North Carolina, and Tennessee. Radial cranial scars were found for 47 individuals, but none of the four cases of dental lesions could be attributed to congenital syphilis. Differences in frequency of cranial lesions by region were minimal, with the least number of cases found for the mountains, but the frequency of positive cases tended to increase through time. It is suggested that increasing population density and changing behaviors, rather than novel strains of the treponemal pathogen, are responsible for the chronological increase in the frequency of positive cases. 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