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Hampshire County was first visited by Europeans around 1725, when explorers followed the Potomac River. Settlers started building homes in the 1730s, and by 1748, about 200 people lived at what would become Romney. In the early 1750s, Fort Pearsall was built to protect settlers from Indian attacks and also housed a school and church.
At this time, the South Branch Valley was part of a land claim by Thomas, Sixth Lord Fairfax. Many settlers were German and worked as tenants on Fairfax's land, though some refused to pay fees. The area was used by Indians for hunting but wasn’t permanently settled by them.
Hampshire County was officially created in 1754, named by Fairfax after Hampshire, England, due to the county's high-quality hogs. It was formed from parts of Augusta and Frederick counties and later contributed to the creation of five other counties. Romney became the county seat, and in 1777, Hampshire had about 3,500 people living in an area of 2,800 square miles.
During the French and Indian War in the mid-1750s, Shawnee Indians, supported by the French, attacked the settlers. Many took refuge in forts like Fort Pearsall, Fort Cocke, and others, until the colonial army secured the area in the late 1750s.