I-85 enters South Carolina along the Vandiver Bridge from Georgia, crossing over Tugaloo River/Lake Hartwell.

Continuing northeast, US 29 joins I-85 (exit 34), near Piedmont, as they run concurrently until after they cross the Saluda River.

Near Spartanburg, I-85 takes a northern bypass of the city with a higher speed limit of 70 mph (110 km/h), while an older alignment designated as I-85 Business (I-85 Bus.)

At milemarker 91 in Gaffney, travelers will not be able to miss the Peachoid, a large water tower with its top shaped like a peach, representing one of the state's most important crops.

[6] The South Carolina Department of Transportation (SCDOT) operates and maintains two welcome centers and five rest areas along I-85.

[7] The South Carolina Department of Public Safety (SCDPS) and State Transport Police (STP) operate and maintain one truck inspection/weigh station, located northbound at milemarker 9 in Fair Play.

[8] The location utilizes weigh-in-motion that does not require commercial motor vehicles to leave the freeway to be weighed.

Established in 1959, I-85 originally ran along the newly widened four-lane section of US 29, from Fort Prince Boulevard (SC 129, exit 68) to the North Carolina state line.

The last original 27 miles (43 km) segment between milemarker 79 and the North Carolina state line is currently in the process of being widened to six lanes, which includes replacing and, in some cases, eliminating many of the previously intriguing exit/entrance ramps.