**Interstate 81** is a north-south interstate in the eastern United States. It runs from Dandridge, Tennessee in the south to Wellesley Island, New York in the north; for a total distance for about 854.89 miles (1,375.81 km). It follows the Appalachian Mountains for nearly its entire length.

Interstate 81 begins in Tennessee at Interstate 40 in Dandridge. The route follows the Appalachian Mountains for much of its route through Tennessee and Virginia, serving such cities as the twin cities of Bristol, Tennessee and Bristol, Virginia, Roanoke, Blacksburg, Lexington, Staunton, Harrisonburg, and Winchester. In Harrisonburg, I-81 cuts through the James Madison University campus. It follows its older counterpart, U.S. Route 11, for its entire length in Virginia.

Interstate 81 briefly enters the eastern panhandle of West Virginia, serving the city of Martinsburg. It then crosses the state of Maryland at one of its narrowest points, passing through the "Hub City" of Hagerstown where it crosses many other routes.

Interstate 81 forms a major north–south corridor through the state of Pennsylvania, serving the boroughs of Chambersburg and Carlisle, where it meets the Pennsylvania Turnpike. But I-81 does not directly interchange with it (motorists must use US 11 to connect). Around the state capital of Harrisburg, the route forms the northeastern section of Pennsylvania's Capital Beltway. The route then travels northeast toward the Wyoming Valley, where it serves the cities of Wilkes-Barre and Scranton, then heads north through the Endless Mountains region toward the state line. Although it is signed as a north–south highway, it is distinctly northeast–southwest and occasionally east–west throughout the state.

Interstate 81 enters the state of New York near Binghamton. It follows U.S. Route 11 in a north–south direction, through much of the state. It serves the cities of Syracuse (where it intersects the New York State Thruway), and Watertown. The route ends at the Canadian border at the Thousand Islands Bridge, where it crosses the St. Lawrence River, continuing as a short connector, Highway 137, which serves the Thousand Islands Parkway and Highway 401.

I-81 looking southbound near milepost 245 in Harrisonburg, Virginia.
The Interstate 81 Corridor Coalition, a six-state coalition, was organized to handle issues along Interstate 81, such as truck traffic and air pollution. As of October 15, 2008, this commission has met twice.

Major intersections
-------------------

* Interstate 40 near Dandridge, Tennessee, northeast of Knoxville, Tenn.
* Interstate 26 between the Tri-Cities, Tennessee
* Interstate 77 and Future Interstate 74 in Wytheville, Va.. They stay joined for about 10 miles (16 km), and go in opposite directions (i.e. this is a wrong-way concurrency, where I-81 North overlaps I-77 South, and vice versa).
* Interstate 64 in Lexington, Va.. They stay joined through Staunton, Va..
* Interstate 66 in Middletown, Va.
* Interstate 70 in Hagerstown, Mary.
* Interstate 76 in Middlesex Township, Pa. (near Carlisle, Pa.)
* Interstate 83 in Harrisburg, Pa.
* Interstate 78 near Jonestown, Pa.)

Approaching the I-78/I-81 interchange in Union Township, Lebanon County, PA).
* Interstate 80 near Hazleton, Pa.)
* Interstate 476/PA Tpk NE Ext. in Dupont, Pennsylvania (near Pittston, Pa.)
* Interstate 84 and Interstate 380 in Dunmore, Pa. (near Scranton, Pa.) Throop Dunmore Interchange
* Interstate 476/PA Tpk NE Ext.(again) in Clarks Summit, Pa.
* Future Interstate 86/NY 17 in Binghamton, NY
* Interstate 88 in Binghamton, NY
* Interstate 690 in downtown Syracuse, NY
* Interstate 90/New York State Thruway in North Syracuse, NY