Region Six, the Mid-South, is located in the southern United States bordered by Mississippi to the east, Arizona to the west and Kansas, Colorado and Missouri to the north. The region consists of the following states: Arkansas, Louisiana, Oklahoma, New Mexico and Texas as well as 66 tribes.

Major water prorities include the Illinois River watershed, the Mississippi River, the Gulf Hypoxia Zone and Coastal Louisiana wetlands. Nutriet loads and contaminated runoff from farm fields are of major conern in this region. Region Six faces a unique set of issues when addressing the Gulf Hypoxia Zone because much of the problem is created by states further up the Mississippi River.