The siege was a part of Pontiac's War, an effort by Native Americans to remove the Anglo-Americans from the Ohio Country and Allegheny Plateau after they refused to honor their promises and treaties to leave voluntarily after the defeat of the French.

This event is known for a possible attempt at biological warfare, in which William Trent and Simeon Ecuyer, a Swiss mercenary in British service, may have given items from a smallpox infirmary as gifts to Native American emissaries with the hope of spreading the deadly disease to nearby tribes.

The effectiveness is unknown, although it is known that the method used is inefficient compared to respiratory transmission and these attempts to spread the disease are difficult to differentiate from epidemics occurring from previous contacts with colonists.

The Forbes expedition was successful in part because of the Treaty of Easton, in which area American Indians agreed to end their alliance with the French.

The proprietor of the Pennsylvania provincial store reported that numerous Delaware warriors had arrived "in fear and haste" to exchange their skins for gunpowder and lead.

The fort's exceptional structural defenses, made of stone with bastions covering all angles of attack, were supported by 16 cannons which he had permanently loaded.

The following day, however, the Shawnee returned and reported a more threatening situation, saying that all the nations "had taken up the hatchet" against the British, and were going to attack Fort Pitt.

Even the local Shawnee themselves "were afraid to refuse" to join the uprising, a subtle hint that the occupants of Fort Pitt should leave.

On June 22, Fort Pitt was attacked on three sides by Shawnee, western Delaware, Mingo and Seneca, which prompted return fire from Ecuyer's artillery.

[5] July 3, four Ottawa newcomers requested a parley and tried to trick the occupants of Fort Pitt into surrender, but the ruse failed.

On July 26, a large conference headed by Ecuyer was convened with several leaders of the Ohioan tribes outside the walls of Fort Pitt.

The Indian delegation, Shingas, Wingenum and Grey Eyes among them, came to the fort under a flag of truce to parley, and again requested that the British leave this place.

This "very much enraged" the Indian delegation, Trent wrote, "White Eyes and Wingenum seemed to be very much irritated and would not shake hands with our people at parting."

[3][8] For Commander-in-Chief, North America Jeffery Amherst, who before the war had dismissed the possibility that the Indians would offer any effective resistance to British rule, the military situation over the summer had become increasingly grim.

Fort Pitt would remain in British hands, and would become a central hub for migrant settlers as they pushed west in ever larger numbers over the next decade.

[14] According to John McCullough, who was held captive, some of the Mahoning village warriors raiding a Juniata settlement caught smallpox from there that then killed some of them.

[15] In 1924 the Mississippi Valley Historical Review published a journal written by William Trent, a fur trader and merchant commissioned as a captain at Fort Pitt.

[27] To Sundries got to Replace in kind those which were taken from people in the Hospital to Convey the Smallpox to the Indians Vizt: 2 Blankets @ 20/ £2" 0" 0 1 Silk Handkerchef 10/ & 1 linnen do: 3/6 0" 13" 6 A month after meeting on July 22, Trent met with the same delegates again and they seemingly had not contracted smallpox: "Gray Eyes, Wingenum, Turtle's Heart and Mamaultee, came over the River told us their Chiefs were in Council, that they waited for Custaluga who they expected that Day.

[12][30] After visiting Pittsburgh a few years later, David McClure would write in his journal published in 1899, "I was informed at Pittsburgh, that when the Delawares, Shawanese & others, laid siege suddenly and most traitorously to Fort Pitt, in 1764, in a time of peace, the people within, found means of conveying the small pox to them, which was far more destructive than the guns from the walls, or all the artillery of Colonel Boquet's army, which obliged them to abandon the enterprise.

[35][1][2][18][15] The account of the British infecting Natives with smallpox during Pontiac's War of 1763 originated with nineteenth century historian Francis Parkman.

[26][25] Following Parkman was Howard Peckham who was more interested in the overall war and paid only cursory glance to the incident, briefly describing Ecuyer handing over the handkerchief and blankets from the smallpox hospital.

[39] Bernhard Knollenberg was more critical and pointed out that both Parkman and Peckham hadn't noticed that the smallpox epidemic among the tribes had been reported to have begun in the spring of 1763, quite some time before the meeting.

[40][12][10] Knollenberg even doubted the authenticity of the documents at first before he was contacted via letter by historian Donald H. Kent who had found a record of Trent's sundries list signed by Ecuyer.

[42] Elizabeth A. Fenn writes that "the actual effectiveness of an attempt to spread smallpox remains impossible to ascertain: the possibility always exists that infection occurred by some natural route.

[45] Researchers James W. Martin, George W. Christopher and Edward M. Eitzen writing in a publication for the US Army Medical Department Center & School, Borden Institute, found that "In retrospect, it is difficult to evaluate the tactical success of Captain Ecuyer's biological attack because smallpox may have been transmitted after other contacts with colonists, as had previously happened in New England and the South.

"[2] In an article published in the journal Clinical Microbiology and Infection researchers Vincent Barras and Gilbert Greub conclude that “in the light of contemporary knowledge, it remains doubtful whether his hopes were fulfilled, given the fact that the transmission of smallpox through this kind of vector is much less efficient than respiratory transmission, and that Native Americans had been in contact with smallpox >200 years before Ecuyer’s trickery, notably during Pizarro’s conquest of South America in the 16th century.