Nine major epidemics of acute infectious diseases swept the Northern Plains of the Western Interior of Canada between 1774 and 1839. The Blackfeet, Plains Cree and Assiniboin, Atsina and Saulteaux who exploited the Plains were differentially exposed to these epidemics of smallpox, measles, whooping cough and influenza. Mortality estimates from these epidemics were used in assessing the degree to which a series of epidemics contributed to depopulation of the Plains Natives. A criteria was established to determine an epidemic from a depopulation epidemic, which involved among other factors, the determination of age-selective mortality. The analysis concludes that despite the fact several Native groups exploited, and in some cases co-resided in a similar ecological area, they suffered differential mortality and depopulation rates.