A state alternate route enters the state from Arkansas and follows US 61, including two overlaps with I-55, all the way to Perryville. The National Route crosses the Mississippi from Illinois on the Chester Bridge, following Route 51 south to Perryville and then turning north along US 61. At exit 170 south of Festus, the Great River Road joins I-55, following that highway into St. Louis and using I-44 and I-70 to exit 220 on the St. Peters-O'Fallon border. From there the National Route follows the entire length of Route 79 to I-72 in Hannibal, where it crosses the Mark Twain Memorial Bridge back to Illinois. A second state alternate begins in Hannibal by running west on I-72 to its end at US 61, then turning north on US 61. It follows Route 168 to Palmyra, rejoining US 61 for the rest of its path to Iowa, except for the portion through La Grange and Canton, where the Great River Road uses the former alignment of US 61, now Route B.