It is estimated to have killed nearly 11,000 Native Americans in the Western area of present-day Washington, reducing the population from 37,000 to 26,000 in just seven years. It affected nearly every tribe on the continent, including the northwestern coast. It also showed up in the interior trading posts of the Hudson's Bay Company in 1782. Beginning in 1780 it reached the Pueblos of the territory comprising present day New Mexico. The disease was likely spread via the travels of the Shoshone Indian tribes. One of the worst tragedies of the pandemic was the massive toll it took on the indigenous population of the Americas. At its end the epidemic had crossed the Great Plains, reaching as far west as the Pacific coast, as far north as Alaska and as far south as Mexico, infecting virtually every part of the continent. By 1779 the disease had spread to Mexico and would cause the deaths of tens of thousands. In the South, it reached Texas, and from 1778 to 1779, New Orleans was especially hard hit due to its densely populated urban area. Many escaped slaves who had fled to the British lines in the South likewise contracted smallpox and died. During Washington's siege of Boston the disease broke out among both Continental and British camps.

In 1775 it was already raging through British-occupied Boston and among the Continental Army's invasion of Canada. The outbreak spread throughout the North American continent. It is not known where the outbreak began, but the epidemic was not limited to the colonies on the Eastern seaboard, nor to the areas ravaged by hostilities. Thus, this virus posed a major threat to the success of the Continental Army, led by George Washington. During this time, there was no medical technology widely available to protect soldiers from outbreaks in crowded and unhygienic troop camps. This epidemic occurred during the years of the American Revolutionary War.

However, there is a period of time in which individuals are contagious but have only begun to experience minor symptoms such as fever, headaches, body aches, and sometimes vomiting. Persons infected with smallpox are infectious to others for about 24 days after their infection time. This limits the chances of the virus being unknowingly spread through contact with insect or other animal populations. Unlike some viruses, humans are the only carriers of variola major. Generally, face-to-face contact is required for an individual to contract smallpox as a result of an interaction with another human. The smallpox virus is transmittable through bodily fluids and materials contaminated with infected materials. The most common type of smallpox, ordinary, historically has devastated populations with a 30% death rate. Smallpox was a dangerous disease caused by the variola major virus.

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