U.S. Route 378 Business (US 378 Bus.) is a business route of US 378 through Lake City. The highway travels from US 378 and South Carolina Highway 341 (SC 341) west of the city to US 378 east of the city. US 378 Bus. begins heading east from US 378 (Turbeville Highway) concurrent with SC 341 along two-lane Main Street. The two highways enter the city just east of Lake City Memorial Park. In the center of the city, US 378 Bus. and SC 341 have an intersection with US 52 (Ron McNair Boulevard). One block after their grade crossing of CSX's Charleston Subdivision, the highways diverge. The main highway continues east on Main Street while the business route turns north onto Church Street. US 378 Bus. leaves the city limits at its crossing of Lake Swamp and reaches its eastern terminus at US 378 (Myrtle Beach Highway).
