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In 1766, Thomas Butler and his brothers were the first permanent European-American settlers in what is now Preston County. Soon, others like Thomas Chipps, Jacob Corzad, John Scott, James Clark, and John (or Jacob) Judy joined them. In 1767, surveyors Charles Mason and Jeremiah Dixon marked the Mason-Dixon Line along the county's northern border. By 1770, other early settlers included Samuel Worral Sr. and his son, Samuel Worral Jr., as well as David Frazee, Richard Morris, and Anthony and Joshua Worley.
By 1782, there were 48 families in the county, with 269 free people and 6 enslaved. The first national census in 1790 showed about 1,000 people living in the county.