U.S. Route 221

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{{Infobox U.S. Route |article_route=221 |type=Secondary |length_mi=734<ref name="droz">Droz, Robert V. US Numbered Highways - The Big Table. URL accessed 21:10, 25 March 2006 (UTC).</ref> |length_km=1,181 |yrcom=1930 (extended north in 1932, 1972, south in 1932, 1954)<ref name="mapguy">mapguy, End of U.S. Highway 221 (with maps of U.S. 221 and related routes). URL accessed 21:00, 25 March 2006 (UTC).</ref> |direction_a=North |direction_b=South |from=Lynchburg, VA |to=Perry, FL }}

U.S. Route 221 is a spur of U.S. Route 21. It runs for 734 miles (1,181 km) from Lynchburg, Virginia at U.S. Route 29 to Perry, Florida at U.S. Route 27. Its passes through the states of Virginia, North Carolina, South Carolina, Georgia and Florida. It goes through the cities of Lynchburg, Virginia, Roanoke, Virginia, Spartanburg, South Carolina, and Valdosta, Georgia.