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First Avenue is a north-south thoroughfare on the East Side of the New York City borough of Manhattan, running from Houston Street northbound to 127th Street. At 125th Street, most traffic continues onto the Willis Avenue Bridge over the Harlem River, which continues into the Bronx.

Like most of Manhattan's major north-south Avenues, First Avenue was proposed as part of the Commissioners' Plan of 1811 for Manhattan, which designated 12 broad north-south Avenues running the length of the island. The southern portions of the Avenue were cut and laid out shortly after the plan was adopted. The northern sections of the Avenue would be graded and cut through at various intervals throughout the 19th century as the northward development of the island demanded.

The IRT Second Avenue Line ran above First Avenue from Houston Street to 23rd Street before turning west at 23rd and then north onto Second Avenue. This elevated line was torn down in 1942.

First Avenue has carried one-way traffic since June 4, 1951.

A protected bike lane was established along the left side of the avenue south of 50th Street in 2011.