Results of protein residue and lithic microwear analyses are reported for Paleoindian and Early Archaic stone tools from a Carolina bay sand rim on the Aiken Plateau of South Carolina, USA. Protein residue analysis is performed using crossover Immunoelectrophoresis (CIEP), and indicates positive results for Bovidae, Cervidae, Galliformes, and Meleagris gallopavo. These results are complemented by a larger immunological study of 135 diagnostic hafted bifaces from South Carolina and Georgia. Among other species identified, bovid residue was found on multiple Paleoindian hafted bifaces, an Early Archaic hafted biface, and a Middle Archaic hafted biface. Results suggest continuity of species selection and availability across the Pleistocene/Holocene boundary and provide no support for the exploitation of extinct fauna. The data do provide compelling evidence for a demographic shift and/or regional extirpation of Bovidae possibly as late as the early mid-Holocene in the Southeast. In addition, microwear analysis of artifacts from Flamingo Bay indicate intensive hide scraping, antler boring, bone graving/planing/pointing, wood whittling, and hafting traces. Microwear data suggest intentional snap-fracture or bipolarization of exhausted or broken Clovis points for reuse as hide scrapers, and use of large bifacial knives and unifacial scrapers in intensive defleshing activities consistent with large animal butchery.