On a number of leading health indicators, including HIV disease, individuals in the southern states of the United States fare worse than those in other regions. We analyzed data on adults and adolescents diagnosed with HIV infection through December 2010, and reported to the Centers for Disease Control and Prevention (CDC) through June 2011 from 46 states with confidential name-based HIV reporting since January 2007 to describe the impact of HIV in the South. In 2010 46.0 % of all new diagnoses of HIV infection occurred in the South. Compared to other regions, a higher percentage of diagnoses in the South were among women (23.8 %), blacks/African Americans (57.2 %), and among those in the heterosexual contact category (15.0 % for males; 88.5 % for females). From 2007 to 2010 the estimated number and rate of diagnoses of HIV infection decreased significantly in the South overall (estimated annual percentage change [EAPC] = -1.5 % [95 %CI -2.3 %, -0.7 %] and -2.1 % [95 % CI -4.0 %, -0.2 %], respectively) and among most groups of women, but there was no change in the number or rate of diagnoses of HIV infection among men overall. Significant decreases in men 30-39 and 40-49 years of age were offset by increases in young men 13-19 and 20-29 years of age. A continued focus on this area of high HIV burden is needed to yield success in the fight against HIV disease.