Interstate 81 (I-81) is a north–south (physically northeast–southwest) Interstate Highway in the eastern part of the United States. Its southern terminus is at I-40 in Dandridge, Tennessee; its northern terminus is on Wellesley Island at the Canadian border, where the Thousand Islands Bridge connects it to Highway 401, the main Ontario freeway connecting Detroit via Toronto to Montreal. The major metropolitan areas that I-81 connects to include Harrisburg in Pennsylvania and Syracuse in New York.

I-81 largely traces the paths created down the length of the Appalachian Mountains by migrating animals, American Indians, and early settlers. It also follows a major corridor for troop movements during the Civil War. These trails and roadways gradually evolved into U.S. Route 11 (US 11); I-81 parallels much of the older US 11. Being mostly rural, it is heavily used as a trucking corridor, often as a bypass of the busier I-95 to the east.

The Interstate 81 Corridor Coalition, a six-state coalition, was organized to handle issues along I-81, such as truck traffic and air pollution; the commission meets annually. I-81 is part of the fastest route between the capital of the United States (Washington, D.C.) and the capital of Canada (Ottawa).

I-81 runs from Interstate 40 at Dandridge, Tennessee, to the Thousand Islands International Bridge at Wellesley Island in New York, beyond which a short stub links it to Ontario Highway 401. In the U.S. state of New York, I-81 extends 183.62 miles (295.51 km) from the Pennsylvania state line southeast of Binghamton to the Canadian border at Wellesley Island northwest of Alexandria Bay. The freeway runs north–south through Central New York, serving the cities of Binghamton, Syracuse, and Watertown. It passes through the Thousand Islands in its final miles and crosses two bridges, both part of the series of bridges known as the Thousand Islands Bridge. South of Watertown, I-81 closely parallels U.S. Route 11 (US 11), the main north–south highway in Central New York prior to the construction of I-81. At Watertown, US 11 turns northeastward to head across New York's North Country while I-81 continues on a generally northward track to the Canadian border. From there, the road continues into the province of Ontario as Highway 137, a short route leading north to the nearby Highway 401.

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