During the late prehistoric period (ad 1250–1550) in the southeast USA, when native populations transitioned to living in permanent, nucleated settlements practicing maize agriculture, most experienced a decline in health. However, some research shows that not all groups experienced the decline in the same way as there were regional differences in dental caries and iron deficiency anaemia frequencies and patterns of physical activity. Therefore, the purpose of this study is to determine if regional differences in health also existed between late prehistoric upland and coastal inhabitants from one part of the southeastern USA. Pathological lesion frequencies were calculated for 441 individuals from 23 upland archaeological sites and compared with previously published data for 340 individuals from 11 coastal sites. Significant differences in lesion frequencies were observed between upland and coastal groups. For example, upland adult men have more carious teeth among the maxillary first incisors, maxillary second molars, mandibular canines, and mandibular second molars. For women, greater caries frequencies are found among the maxillary first and third molars, mandibular first incisors, and mandibular third premolars. Upland children show higher percentages of caries for 14 tooth classes. Coastal juveniles have a greater frequency of porotic hyperostosis, and more of them exhibit an enamel hypoplasia. Periosteal lesion frequency is greater for the coastal group at the humerus, radius, femur, and tibia. Lesions indicative of degenerative joint disease are more often found on the thoracic spinal segment, sacrum and shoulder of upland men with upland women having more lesions at the cervical, thoracic, and lumbar spinal segments, the sacrum, and the shoulder. Taken together, these results show that adults from the upland region consumed more maize and lived a more physically demanding life while coastal adults struggled more with infection. Among children, more coastal inhabitants were anaemic and more of the experienced significant growth disturbances. Copyright © 2013 John Wiley & Sons, Ltd.