Major Intersections
US 281 intersects with the following Interstate Highways:
- Interstate 94 in Jamestown, North Dakota
- Interstate 90 near Plankinton, South Dakota
- Interstate 80 in Grand Island, Nebraska
- Interstate 70 in Russell, Kansas
- Interstate 40 in Hinton, Oklahoma
- Interstate 44 between Wichita Falls, Texas and a point near Medicine Park, Oklahoma (co-signed route)
- Interstate 20 south of Mineral Wells, Texas
- Interstates 10, 410, 35, and 37 in San Antonio
- Interstate 37 between Pleasanton and Three Rivers, Texas (shared route)
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