U.S. 221 in the Palmetto State travels 126.39 miles north from the Georgia line across Clark Hill Lake into North Carolina beyond Chesnee. U.S. 221 joins the McCormick County seat of McCormick with the city of Greenwood to the northeast. Crossing Lake Greenwood into Laurens County, U.S. 221 continues northward to Laurens, Woodruff and into Downtown Spartanburg.
The original south end of U.S. 221 was located at U.S. 25 in the city of Greenwood. A joint effort by the South Carolina Department of Highways, The State Highway Department of Georgia and State Road Department of Florida requested an extension of U.S. 221 south to Perry, Florida to the American Association of State Highway Officials (AASHO). Approved on November 13, 1953, the application outlined 33.976 miles in Florida, 258 miles in Georgia and 44 miles in South Carolina. Among other reasons, Georgia cited in a letter to AASHO on September 29, 1953:
There is a definite need for another U.S. Numbered Route from South Carolina into Georgia that will avoid the traffic congestion in Augusta and Savannah. This is evidenced by the fact that when U.S. Route 301 was approved August 28, 1947, the traffic volume at the South Carolina - Georgia line was approximate 500 vehicles per day, and by 1952 this volume had increased to an annual average of 2900 vehicles per day.
Within the Palmetto State, U.S. 221 overtook S.C. 10 from Greenwood south to Bradley, S.C. 670 from S.C. 10 to McCormick and overlaid S.C. 28 from McCormick to Clark Hill Dam crossing the Savannah River west of Clarks Hill.
U.S. 221 was rerouted to circumvent Greenwood on a bypass completed in Summer 1968. The former route was designated as U.S. 25/178 Business. Further realignment shifted U.S. 221 onto S.C. 670, replacing the state highway northeast to U.S. 25/178 and established U.S. 221 Business to S.C. 72 Bypass. AASHO approved the changes on October 14, 1967.
North
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This sign bridge preceding the turn of U.S. 221 north onto Whitney Road from Church Street was removed by 2021.
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South
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U.S. 221 turns south onto Church Street from Whitney Road just beyond the exchange with I-585/U.S. 176/S.C. 9 (N Pine Street).
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U.S. 221 (Church Street) intersects Catawba Street at Spartanburg Medical Center hospital.
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Curving southeast toward Downtown Spartanburg, U.S. 221 (Church Street) converges with S.C. 56 (Asheville Highway) eastbound.
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S.C. 56 (Asheville Highway) runs northwest to Lone Oak, Southern Shops and U.S. 176 (N Pine Street) beyond Interstate 85.
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South 
East
U.S. 221/S.C. 56 overlap 1.29 miles south along Church Street to E Henry Street.
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Evins Street stems east from Church Street onto the campus of Wofford College.
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Daniel Morgan Avenue was formerly part of S.C. 296. S.C. 296 branches west from U.S. 29 (W Main Street) along John B. White, Sr. Boulevard to I-26 at Exit 22.
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Connect with:
Interstate 26
Interstate 85
Interstate 385
Interstate 585 / U.S. 176
U.S. 25
U.S. 29
U.S. 76
U.S. 176
Page Updated 03-09-2022.