South Carolina Highway 381 (SC 381) is a 22.700-mile (36.532 km) primary state highway in the U.S. state of South Carolina. It connects the towns in eastern Marlboro County.

SC 381 traverses from Blenheim at SC 38 to the North Carolina state line where it continues as North Carolina Highway 381 into Gibson, North Carolina. As a two-lane rural highway, it connects the towns of Clio and McColl.

The highway was established in 1930 as a new primary route from SC 38 in Blenheim to SC 9 in Clio. In 1931 or 1932, it was extended north to SC 30 (today U.S. Route 15 (US 15) and US 401) in McColl; and west to the community of Marlboro. In 1934, the western extension was dropped while it extended north again to the North Carolina state line. In 1940, SC 381 was extended west again to SC 382 in Scott, only to be truncated back in Blenheim by 1948.

This section is missing mileposts for junctions. Please help by adding them.

The entire route is in Marlboro County.

Location	mi	km	Destinations	Notes
Blenheim	0.000	0.000	SC 38 (Main Street) – Bennettsville, Marion	Southern terminus
​			I-73	Proposed interchange
Clio	8.390	13.502	SC 9 (Main Street) – Bennettsville, Dillon
​	9.850	15.852	SC 83 north – Maxton	Southern terminus of SC 83
McColl	15.630	25.154	US 15 / US 401 (Tatum Avenue) – Bennettsville, Laurinburg
​	22.700	36.532	NC 381 north (Church Street) – Hamlet	Continuation into North Carolina
1.000 mi = 1.609 km; 1.000 km = 0.621 mi       Unopened

• U.S. roads portal

• Media related to South Carolina Highway 381 at Wikimedia Commons
• SC 381 at Virginia Highways' South Carolina Highways Annex