Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) continue to be a significant public health concern in the United States. It disproportionately affects persons in the Deep South of the United States, specifically African Americans. This is a descriptive report of an Emergency Department (ED)-based HIV screening program in the Deep South using the 2006 Centers for Disease Control and Prevention (CDC) recommendations for rapid testing and opt-out consent. Between May 2008 and March 2010, patients presenting for medical care to the ED Monday through Friday between 10 AM and 10 PM were approached for HIV screening. Patients were eligible for screening if they were 18 or older, had no previous history of positive HIV tests, were English-Speaking, and were not incarcerated, medically unstable, or otherwise able to decline testing. All patients were tested using the OraQuick® rapid HIV 1/2 antibody test. Patients with non-reactive results were referred to community anonymous testing sites for further testing. Patients with reactive results had confirmatory Western blot and CD4 counts drawn and were brought back to the ED for disclosure of the results. All patients with confirmed HIV positive via reactive Western blot were referred to the hospital-based infectious disease clinic or county health department. We tested 7,616 patients out of 8,922 approached. The overall test acceptance rate was 85.4%. 91.0% of patients tested were African American. The most common reason for refusal was recent HIV test. 1.7% of patients tested were confirmed HIV positive via Western blot. 95.2% of patients testing HIV positive were African American. The average CD4 count for patients testing positive was 276 cells/μl, with 42.0% of patients having CD4 counts ≤200 μl, consistent with an AIDS diagnosis. 88.4% of patients who had reactive oral swabs returned for Western blot results and 75.0% of patients attended their first clinic visit. We have been able to successfully carry out an ED-based HIV screening program in a resource-poor urban teaching facility in the Deep South. We define our success based on our relatively high test acceptance rate and high rate of attendance at first clinic visit. Our patient population has a relatively high undocumented HIV prevalence and are at advanced stage of disease at the time of diagnosis.