The greatest loss of life for the Native peoples in the 16th and 17th centuries would be smallpox. They did not have this natural immunity that the Europeans did and thousands died as a result.
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The greatest loss of life for Native Americans during the 16th-17th centuries caused by Infectious Diseases brought by Europeans.
Decimation of buffalo herds
Smallpox was by far the most dangerous disease, for native Americans, once it was introduced to the western hemisphere by European colonists.
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