U.S. Route 278 (US 278) is a 146.130-mile (235.173 km) east–west United States highway that traverses through the South Carolina Lowcountry, from North Augusta to Hilton Head Island.

It then forms a de facto northern boundary of the Savannah River Site, crossing into the property on a few occasions.

The route then continues eastward and then southward through the communities of Barnwell, Kline, Allendale, Fairfax, Hampton, Varnville, Ridgeland, and Hardeeville where it meets I-95.

After a five-mile stretch in which the route is tolled, US 278 ends at US 278 Business on the southern portion of Hilton Head Island, just outside Sea Pines Plantation.

[citation needed] Before the toll road opened, it could take one hour to travel the 12-mile (19 km) route of what was then signed as US 278 (William Hilton Parkway) during peak tourism season.

Those that did not have exact change or do not pay the toll had five days to contact the Cross Island Parkway Customer Service Center to make a payment; after that time, a violation notice was mailed.