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In Washington, D.C., Independence Avenue is a major east-west street running just south of the United States Capitol in the city's Southwest and Southeast quadrants. The avenue carries heavy commuter traffic on weekdays and heavy tourist traffic on the weekends.

In Washington's Cartesian-coordinate-based street-naming system, Independence Avenue was originally known as South B Street. If it had stayed in the city's lettered street system, it would today be known as B Street, S.W. and S.E. However, Constitution Avenue was originally known as North B Street, and having two major streets running so close together in parallel, both called B Street, would presumably be too confusing for many people. However, the street on the other side of the Anacostia River corresponding to Independence Avenue is called B Street, S.E.

The western terminus of Independence Avenue is at 23rd Street, S.W., south of the Lincoln Memorial. At that terminus, Independence Avenue joins Ohio Drive, which connects the avenue with the Rock Creek and Potomac Parkway, Interstate 66, the E Street Expressway, and the Whitehurst Freeway. At the eastern terminus, Independence Avenue curves around the Robert F. Kennedy Memorial Stadium to join the Whitney Young Memorial Bridge.

Because Independence Avenue forms the southern boundary of the National Mall, it is lined on the north side by several Smithsonian museums and on the south side by federal agencies, including the United States Department of Agriculture (USDA), Department of Health and Human Services, Federal Aviation Administration, Coast Guard, and the United States Department of Energy. The USDA occupies buildings on both sides of the avenue, connected by a pedestrian bridge over the avenue. Independence Avenue also passes by the United States Botanic Garden, the House office buildings and the Library of Congress and through the city's Capitol Hill and Lincoln Park neighborhoods.

Memorials along Independence Avenue include the Korean War Veterans Memorial, the District of Columbia War Memorial, the John Paul Jones Memorial, and the United States Holocaust Memorial Museum.

From 23rd Street, S.W., to Pennsylvania Avenue, S.E., Independence Avenue is part of the National Highway System. Other major traffic routes intersecting the avenue are Maine Avenue and Washington Avenue, the latter of which is a short segment of the National Highway System connecting to South Capitol Street.