I-81 crosses the New York–Pennsylvania border about southeast of the city of Binghamton. The freeway heads northwest from the state line, running through a valley surrounding the Susquehanna River in the town of Kirkwood. This stretch of I-81 closely parallels US 11, continuing a trend that originally began at I-81's southern terminus in eastern Tennessee. Both roads head across relatively undeveloped areas along the eastern riverbank to the outskirts of Binghamton, where I-81 merges with New York State Route 17 (NY 17) (Future I-86) in an industrial area east of the city. I-81 and NY 17 overlap for , running along the northern edge of the Binghamton suburbs before entering the city itself. About north of downtown, the freeway connects to Brandywine Highway, a limited-access road carrying NY 7 through mostly residential areas on the north side of the city.