Fort Defiance (Illinois) in the context of Illinois Department of Natural Resources

Cairo (/ˈkɛəroʊ/ KAIR-oh, sometimes /ˈkeɪroʊ/ KAY-roh) is the southernmost city in the U.S. state of Illinois and the county seat of Alexander County. A river city, Cairo has the lowest elevation of any location in Illinois and is the only Illinois city to be surrounded by levees. The city is named after Egypt's capital on the Nile and is located in the river-crossed area of Southern Illinois. It is coterminous with Cairo Precinct.

Cairo is located at the confluence of the Ohio and Mississippi rivers, the largest rivers in North America, and is near the Cache River complex, a Wetland of International Importance. Settlement began in earnest in the 1830s and busy river boat traffic expanded through the 1850s. Fort Defiance, a Civil War base, was located here in 1862 by Union General Ulysses S. Grant to control strategic access to the rivers and launch and supply his successful campaigns south. The town also served as a naval base for the Mississippi River Squadron to pursue the Anaconda Plan to win the war. Developed as a river port, Cairo was later bypassed by transportation changes away from the large expanse of low-lying land, wetland, and water, which surrounds Cairo and makes such infrastructure difficult, and due to industrial restructuring, the population peaked at 15,203 in 1920, while in the 2020 census it was 1,733.