U.S. Route 221 is a spur of U.S. Route 21. It runs for 734.75 miles (1,182 km) from Perry, Florida, at U.S. Routes 19/98/27 Alternate to Lynchburg, Virginia, at U.S. Route 29 (Lynchburg Expressway). It passes through the states of Florida, Georgia, South Carolina, North Carolina, and Virginia. It goes through the cities of Valdosta, Georgia; Spartanburg, South Carolina; Marion, North Carolina; Roanoke, Virginia; and Lynchburg, Virginia.
|South end:||US 19 / US 27 Alt. / US 98 / SR 55 in Perry, FL|
|North end:||US 29 Bus. / US 460 Bus. / US 501 Bus. at Lynchburg, VA|
|Highway system||NY 104 at the Canadian border in Niagara Falls, NY||States||Florida, Georgia, South Carolina, North Carolina, Virginia|