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The earliest documented epidemic in Oregon was smallpox.

The loss of population resulted in abandoned and consolidated villages, the breakdown of social and political structures, and the loss of cumulated knowledge possessed by specialists (in a culture without written records), making the epidemics cultural as well as biological disasters. Cumulative evidence suggests that cultural unfamiliarity with the new diseases-that is, people did not know how to treat them-and the lack of effective medicines may have been as or more important than biological resistance, genetic or acquired, in accounting for the high mortalities. Whenever the first epidemics appeared, they had wide-ranging effects far beyond demographic decline. It has been hypothesized that Oregon and the West Coast participated in the first great pandemic of introduced epidemic disease-smallpox in 1519 and the years following (introduced to the mainland concurrent with Cortez's conquest of Mexico)-but there is no definitive proof of this anywhere in the Northwest. Among these, half appeared in epidemic form in Oregon during the first century of contact, from the late 1700s through the mid-1800s. The most deadly were smallpox, malaria, viral influenza, yellow fever, measles, typhus, bubonic plague, typhoid fever, cholera, and pertussis (whooping cough). The list of diseases introduced to the New World is long, and nearly all that could be supported in a temperate environment appeared in present-day Oregon. The interhemispheric disease exchange resulted in what has been called the "greatest demographic disaster in human history." Millions died. When the new diseases spread to the Americas and to peoples who had never experienced them before, the results were dramatic and sometimes catastrophic. In the Old World, epidemic crowd diseases had evolved along with the earliest civilizations, but they had no equivalents in the New World. One of the most profound and far-reaching effects of that exchange concerned microorganisms and the diseases they caused.

In 1972, historian Alfred Crosby introduced the term Columbian Exchange to refer to the interchange of plants, animals, bacteria, and peoples that occurred between the Old World (Eurasia and Africa) and the New World (the Americas and Australia) following the arrival of Christopher Columbus in the Americas in 1492.