We examine epidemiological and demographic data documenting the HIV/AIDS epidemic in the Deep South region of the United States. These data document substantial increases in AIDS cases in the Deep South from 2000 to 2003. In contrast, other US regions are experiencing stable rates or small increases in new AIDS cases. Furthermore, the AIDS epidemic in the Deep South is more concentrated than in other regions among African Americans, women, and rural residents. The Deep South also has some of the highest levels of poverty and uninsured individuals, factors that complicate the prevention and treatment of HIV infection. Further research is needed to determine the cause of the disproportionate rise in AIDS incidence and to develop effective means of preventing HIV infection and providing care of those infected in this region.