Several special routes of U.S. Route 61 exist in the states of Louisiana, Mississippi, Missouri, and Iowa.

U.S. Highway 61 (US 61) is a United States Highway that serves eastern Iowa. It enters the state from Missouri near Keokuk with US 136. North of Keokuk, it is overlapped by US 218 for a few miles. It the follows the course of the Mississippi River past Montrose and Fort Madison. It meets US 34 at Burlington. It passes through Wapello and bypasses Muscatine and Blue Grass on its way toward Davenport. There, it follows Interstate 280 (I-280) and I-80 around the Quad Cities. North of Davenport, it follows a freeway north toward DeWitt where it meets US 30. The highway continues north through Maquoketa and reaches the Dubuque area. There it is joined by US 151 and briefly by US 52. The two highways enter the downtown area on an expressway. Due to the proximity of the Mississippi River and railroad tracks that lie between, the routes have an indirect junction with US 20. The two highways leave the state and enter Wisconsin about one-half mile (800 m) north of the Illinois–Wisconsin state line.