 The highway connects North Central Florida with Upstate South Carolina.US 221 has concurrencies with Georgia State Route 76 (SR 76) from the Florida state line to Quitman, SR 333 within Quitman, SR 38 from Quitman to Valdosta, SR 7 in Valdosta, SR 31 from Valdosta to Douglas, SR 135 in Lakeland, SR 37 from Lakeland to east of Lakeland, SR 122 from Lakeland to northeast of Lakeland, SR 135 Byp.in Lakeland, SR 135 from Douglas to Uvalda, SR 32 Truck/SR 158 Truck and SR 32 in Douglas, SR 135 Conn. in Hazlehurst, SR 56 from Uvalda to Gillis Springs, SR 15 in Soperton, SR 171 from Gillis Springs to Louisville, SR 78 within the vicinity of Bartow, SR 47 within the vicinity of Louisville, SR 4 Bus.