U.S. Route 221 (US 221) is a part of the United States Numbered Highway System that travels from Perry in North Florida to Lynchburg in Central Virginia. In South Carolina, the highway travels 126.390 miles (203.405 km) south to north from the Georgia state line south of Modoc to the North Carolina state line near Chesnee. While in the state, the highway travels through Greenwood, Laurens, Woodruff, and Spartanburg. The highway mostly travels through rural parts of the Piedmont region of the state.