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The nearest sizable city to the park in North Carolina is Asheville. Asheville is about 50 miles east of Cherokee and the Oconaluftee Visitor Center. It takes a little over an hour to get from Asheville to the Cherokee entrance of the park, via Interstate 40 and U.S. Highways 19 and 441. The closest sizable city to the park in Tennessee is Knoxville, about 40 miles west of the Sugarlands entrance, via U.S. Highway 441.

Coming either from the east or west, Interstate 40 is the main interstate access route to the Great Smokies; from the north and south, Interstate 75, Interstate 81, and Interstate 26 are primary arteries.

U.S. 441, also called Newfound Gap Road, is the main road through the park, and the only paved road that goes all the way through. It travels 31 miles between Cherokee and Gatlinburg, crossing Newfound Gap at nearly a mile high.

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