Approximately one million persons infected with human immunodeficiency virus (HIV) live in Ethiopia. Socio-cultural factors influence prevention and treatment adherence. We applied a qualitative descriptive approach to evaluate community perception, knowledge, and the role of spiritual factors in regard to HIV. We conducted 14 focus groups with sampling of HIV+ and HIV- participants (n = 52) by using open-ended questions. We coded and analyzed data for major themes. There are misconceptions, including transmission via casual contact, and pervasive beliefs of holy water as a cure. Many HIV-participants believe treatment is ineffective or incompatible with holy water. Most HIV+ participants believe treatment and holy water can be taken together, but experienced either pressure to stop treatment or stigma when taking medications. Participants emphasized the role of spiritual leaders in directing and shaping community perspectives on HIV. Ongoing community education via local initiatives, nation-wide structural and environmental strategies, and efforts tailored toward Ethiopian society to reconcile treatment with faith are crucial.