Adherence to HIV medications has been an important focus over the past decade, but little is known about adherence barriers and facilitators specifically in that part of the United States known as the Deep South. Characteristics of the region may affect factors associated with adherence related to the patient, the patient-provider relationship, and the environment. A total of 20 HIV-infected clients of a large public infectious diseases clinic in the Deep South participated in one of three focus groups; themes were identified by content analysis. Barriers included the perceived burden of extra planning, denial, life stress, difficult characteristics of the medicines, social stigma, and shame. Facilitators included acceptance of the diagnosis, thinking about the consequences of not taking the medicines, prayer and spirituality, improvements in the medicines, and support from family and friends. In the South, faith and prayer may be strong facilitators that need to be considered when adapting existing adherence interventions.