Exogenous diseases represent one of the principal agents of culture change associated with the historic period, yet the timing of their initial influence remains undocumented in many regions of North America. Settlement variables, cooking pot volume, and mortality profiles from Oneota tradition occupations are used to investigate the possible occurrence of epidemics in the Upper Mississippi River valley. Synchronous fluctuations in settlement and ceramic variables indicate that following at least two centuries of population growth a significant population decline occurred in the early seventeenth century. Several factors provide support for the role of disease in this decline, including its timing, magnitude, and the documented presence of epidemics in adjacent regions combined with substantial evidence for extensive contact with those areas. This event, prior to direct, sustained contact, is associated with the increased intensity of intergroup exchange occurring with the fur trade. The ability to identify the occurrence of such epidemics is essential for understanding protohistoric cultural dynamics as well as the transmission of disease on a continental level.