All four route classes utilize letter suffixes in some form across the United States. Cases for suffixed routes include the scenario where a highway divides into two alternative routes and neither route is considered to be the “main” route. U.S. 49E (east) and 49W (west) in Mississippi, where the east branch serves Greenwood and the west branch serves Indianola, is an example of this.

Another instance occurs along state and county roads when a route separates into multiple segments. Mississippi 9W provides a west branch of SR 9 to Oxford for instance, while three respective branches of Santa Rosa County 191 in Florida are signed as 191A, 191B and 191C.

Most suffixed routes in the Interstate Highway System were eliminated due to motorist confusion as advocated by AASHTO starting in 1973. Exceptions until 2012 included the two partitions of Interstate 35 at Minneapolis/St. Paul and Dallas/Fort Worth. The Congressionally designated IH 69 corridor in South Texas designated three new suffixed routes.