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I-20 dives into Oxford from the west into its interchange with Alabama State Route 21 (SR 21). Here, you can see Quintard Mall and some of the highest mountains in Alabama, including Cheaha Mountain. The Anniston–Oxford metropolitan area is served by exits 179, 185, 188, and 191.

01928-01-01. 1928. 01957-01-01. 1957. Section from Lowndesboro to the Florida state line replaced by SR 209 and parts of SR 28 and SR 43 (this section became SR 41 in the 1957 renumbering) in 1955/1956; rest renumbered as part of SR 21 because of US 11. SR 12. 231.682. 372.856. US 84 at the Mississippi state line.

Anniston is the county seat of Calhoun County in Alabama and is one of two urban centers/principal cities of and included in the Anniston-Oxford Metropolitan Statistical Area. As of the 2010 census, the population of the city was 23,106. According to 2019 Census estimates, the city had a population of 21,287.

Then, after diverting from I-20 east of Oxford at exit 191, it reverts to a two-lane highway southward to Opelika, with a brief four-lane stretch just south of Wedowee. From Opelika southward to its southern terminus in Dothan, US 431 is now open as a four-lane highway. Anniston Eastern Bypass