Mississippi Highway 16 is a state highway in central Mississippi. It runs east–west for 186.4 miles (300.0 km), from the Mississippi Delta region to the Alabama state line. MS 16 serves 8 counties: Issaquena, Sharkey, Yazoo, Humphreys, Madison, Leake, Neshoba, and Kemper.

Issaquena County is a county located in the U.S. state of Mississippi. As of the 2020 Census, its population was 1,338, making it the least populous county in the United States east of the Mississippi River. Its county seat is Mayersville. With a per-capita income of $18,598, Issaquena County is, by that measure, one of the poorest counties in the United States.