Interstate 81 (I-81) is an 855.02-mile-long (1,376.02 km) Interstate Highway. In the US state of Virginia, I-81 runs for 324.92 miles (522.91 km), making the portion in Virginia longer than any other state's portion of the route. It is also the longest Interstate Highway within the borders of Virginia. It stretches from the Tennessee state line near Bristol to the West Virginia state line near Winchester. It enters Virginia from Bristol, Tennessee, and leaves Virginia into Berkeley County, West Virginia. The route passes through the cities of Bristol, Roanoke, Lexington, Staunton, and Harrisonburg.

Winchester is the northwesternmost independent city in the Commonwealth of Virginia, United States. It is the county seat of Frederick County, although the two are separate jurisdictions. As of the 2020 census, the city's population was 28,120. It is the principal city of the Winchester metropolitan area with a population of just over 145,000 extending into West Virginia, which is a part of the Washington–Baltimore combined statistical area. Winchester is home to Shenandoah University and the Museum of the Shenandoah Valley.