The disease particularly impacts the Ojibwe, Shoshone, Siksika, Kanai, Peigan, Cree, Assiniboine, and A'aninin people across North Dakota, South Dakota, Minnesota, and Wisconsin, as well as First Nations communities in what is known today as Canada.

Up until this devastation, Great Lakes Indigenous communities had managed to maintain traditional practices and remain culturally separate from white communities, and trading on their own terms. After the impact of smallpox, survivors became more dependent on settler economies.