Throughout western North Carolina, from the Virginia state line to the Blue Ridge Parkway, US 221 is a challenging drive, and can be described as one climb after another.[citation needed][neutrality is disputed] In some places, the route skirts around large foothills.
In Douglas, U.S. Route 221 runs as the eastern part of Bowens Mill Rd. and will be widened in the future. It passes through Hazelhurst, Mount Vernon and Soperton before crossing Interstate 16, then later joins up with U.S. Route 1 and Georgia State Route 4 after passing through Louisville. After going through Wrens, it splits off to the north, cosigned with Georgia State Route 47 and passes through Harlem before crossing Interstate 20 /Georgia State Route 402 approximately 20 miles west of Augusta. Shortly before crossing into South Carolina, Georgia State Route 150 merges with Route 221 at the Pollards Corner intersection as Georgia 47 turns away. The passage into South Carolina takes place on top of the J. Strom Thurmond Dam, which forms the southern shore of Lake Strom Thurmond.
U.S. Route 221 enters South Carolina in rural McCormick County at the southeastern edge of Lake Strom Thurmond. It continues north and northwestward to the town of McCormick. From McCormick, it continues northerly to the city of Greenwood.
From Greenwood, U.S. Route 221 continues northeasterly to the city of Waterloo, South Carolina. U.S. Truck Route 221 bypasses the city of Laurens on the east side. It continues northerly and intersects Interstate 385 in rural Laurens County and proceeds to intersect Interstate 26 in rural Spartanburg County.
U.S. Route 221 continues through the center of the city of Spartanburg before intersecting Interstate 85 just north of the city. It continues to the city of Chesnee before exiting the state in a rural area of Cherokee County. The southern terminus of U.S. Alternate Route 221 intersects the main route in the city of Chesnee and exits the state a few miles to the east of the main route.
US 221 is a major highway in Western North Carolina. It runs through the cities and towns of Rutherfordton, Marion, Blowing Rock, Boone, and Jefferson. The highway is predominantly two-lane, while four-lane in Marion, Blowing Rock, and Boone. The section from the U.S. Route 321 interchange just east of Boone and into Jefferson in Ashe county is now a divided, four-lane controlled-access road, making this section a much more pleasant and scenic one. Two sections of the highway can be considered challenging and twisty: 13-mile stretch between Linville and Blowing Rock, and a 21-mile stretch between Jefferson and Twin Oaks.
U.S. Route 221 has one Alternate (continuing from South Carolina) and two Business Routes (in Marion and Jefferson). It intersects two major highways: U.S. Route 74 near Rutherfordton and I-40 near Marion; and also intersects with the Blue Ridge Parkway four times.
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