Interstate 81 (I-81) is an 846-mile (1,362 km) long highway. In the U.S. state of Virginia, I-81 runs for 324.92 miles (522.91 km), making it longer in Virginia than in any other state. It stretches from the Tennessee state line near Bristol to the West Virginia state line near Winchester. For most of its length, U.S. Route 11 parallels I-81.

I-81 runs concurrently with Interstate 77 in Wytheville, Virginia for about 10 miles (16 km) in a notable example of a wrong-way concurrency: both I-81 South and I-77 North share the same roadbed there.

The state has proposed to widen its entire portion of I-81 to a minimum of three or four lanes in each direction to accommodate increased truck traffic and to toll non-passenger vehicles. Some sections of the new Virginia I-81 may completely separate car and truck traffic.