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In 1763, a particularly serious uprising threatened the British garrisons west of the Allegheny mountains. Worried about his limited resources, and disgusted by what he saw as the Indians’ treacherous and savage modes of warfare, Sir Jeffrey Amherst, commander-in-chief of British forces in North America, wrote as follows to Colonel Henry Bouquet at Fort Pitt: "You will do well to try to inoculate the Indians [with smallpox] by means of blankets, as well as to try every other method, that can serve to extirpate this execrable race."

Bouquet clearly approved of Amherst's suggestion, but whether he himself carried it out is uncertain. On or around June 24, two traders at Fort Pitt did give blankets and a handkerchief from the fort’s quarantined hospital to two visiting Delaware Indians, and one of the traders noted in his journal: "I hope it will have the desired effect." Smallpox was already present among the tribes of Ohio; at some point after this episode, there was another outbreak in which hundreds died.