U.S. Route 221 Truck directs truck drivers, that are passing through, to follow US 19 going northwest of Perry, then crosses back to US 221 via County Road 359A.
Hazlehurst truck route
U.S. Route 221 Truck is a truck route that directs truck drivers away from the local streets of Hazlehurst, Georgia, including the one-way pair section of US 221 and Georgia State Route 135. It begins on East Jefferson Street from US 221/SR 135. It is concurrent with SR 135 Connector. When SR 135 Conn. ends at US 23/SR 19, US 221 Truck/SR 135 Truck turn left onto the US 23/SR 19 concurrency known as Larry Contos Boulevard, and then turns left onto US 341/SR 27 eventually terminating at northbound US 221. The highway is entirely concurrent with SR 135 Truck.
Laurens truck route
U.S. Route 221 Truck directs truck drivers away from the local streets of Laurens, South Carolina, along SC 127 and part of U.S. Route 76.
U.S. Route 221 Alternate was established in 1941 when mainline US 221 was realigned further west along a straight route between Chesnee and Rutherfordton. Starting in Chesnee, the alternate route follows the original route going east to Cowpens National Battlefield before going north into North Carolina; it then goes through the communities of Cliffside, Henrietta, Caroleen, and Alexander Mills before reaching Forest City. At Forest City, it goes west to Spindale then finally in Rutherfordton, where it reconnects with main US 221. In 1971, US 221A alignment was adjusted in Cliffside. In South Carolina it has an alternate plate above the shield, while in North Carolina an "A" is affixed in the shield.
U.S. Route 221 Business, established in 1991, is a business loop through downtown Marion, via Main Street. It follows the old US 221 alignment before it was rerouted onto Marion Bypass, located west of the city. It also shares a partial overlap with US 70 north of the city center area.
Linville–Boone truck route
U.S. Route 221 Truck provides an alternate route for truck drivers between Linville and Boone, via NC 105. It avoids an drive of endless curves and constant elevation changes along a stretch of US 221 between Linville and Blowing Rock, dubbed the Little Parkway Scenic Byway. In Boone, the truck route overlaps with US 321 Truck and US 421 Truck.
Jefferson business loop
U.S. Route 221 Business, established in November, 1981, is a business loop through West Jefferson and Jefferson. Sharing partial overlaps with NC 194 and NC 88, it follows the original US 221 alignment before it was rerouted onto new bypass route east of the towns in September, 1981.
Bedford business loop
U.S. Route 221 Business, established in 1999, this route follows the old mainline US 221 through the town of Bedford.
