U.S. Federal Route 278 runs north-south from the Coahoma/Bolivar County Line to near Lyon. At Lyon is runs east-west to the Coahoma/Quitman County Line. U.S. Rt. 278 passes through the following town in Coahoma County. Clarksdale
U.S. Rt. 278 is multi-plexed in Coahoma County. U.S. Rt. 61, from the Coahoma/Bolivar County Line to near Lyon.
NB U.S. Rt. 49/61; EB U.S. Rt. 278 near Clarksdale. A BGS on NB U.S. Rt. 49/61; EB U.S. Rt. 278. EB U.S. Rt. 278/MS St Rt 6 east of U.S. Rt. 49/61. WB U.S. Rt. 278/MS St Rt 6 at the Coahoma/Quitman County Line.