Shelby County, Tennessee has the fastest growing rate of HIV infection in the state, and the majority of new infections are in African Americans. In 2011, a Centers for Disease Control and Prevention report stated that Memphis (the largest city in Shelby County) ranked seventh highest in new HIV infections. Little research has addressed HIV-related themes in African American culture that could hinder HIV prevention measures. Our qualitative study engaged African American, faith-based leaders in areas with high rates of HIV in meaningful conversations regarding their attitudes toward HIV and those who are infected. Although faith-based leaders felt they had a role in HIV prevention, only 4% in our study had participated in HIV prevention activities, but they were open to HIV prevention programs. We found that faith-based leaders had limited knowledge of health disparities and ongoing stigma concerning HIV, which served as a major barrier to HIV prevention.