Although Euro-African diseases were slow in entering the North Carolina interior, their end result was no less devastating than if they had swept across the foothills with the arrival of the early Spanish explorers. By 1740, when the first white settlers began venturing into the northern piedmont, they met no resistance from the native tribes. In fact, they met few natives. Over a period of less than 100 years after the first Virginia traders bartered their wares, the villages of the Sara, Occaneechi, Eno, Sissipahaw, Tutelo, Saponi, and Shakori lay vacant, surrounded by abandoned fields that were soon to be tilled by the newcomers.

There can be no argument that alien diseases were a major cause of depopulation and the cultural demise of Southeastern Indians; however, to view the spread of these diseases as waves of uninterrupted pandemics during the sixteenth century oversimplifies complex processes of culture contact and change. Many factors contributed to the spread and "deadliness" of Old World microbes, including native population densities, the intensity of interaction between tribes and newcomers, and intertribal relations. The etiology of the various diseases also must be considered in conjunction with geographic and topographic factors.

In short, a complex of many cultural, social, and biological variables contributed to the timing and rate of depopulation in the Southeast. It is far too simplistic to place most of the blame on the sixteenth-century Spanish explorers. They, no doubt, contributed their share in some parts of the Southeast, but it was the late seventeenth-century English traders who introduced the Carolina Piedmont Indians to these deadly, invisible invaders.