PURPOSE: The WHOQOL instruments are intended for cross-cultural studies of quality of life (QoL) but African countries have been poorly represented in its development. This study aimed to explore the conceptual equivalence of WHOQOL-HIV in Ethiopia. METHODS: The fieldwork included home visits, interviews, and focus group discussions with HIV patients and caregivers. RESULTS: We found that although WHOQOL-HIV includes many relevant facets, its applicability has several limitations in the Ethiopian setting. The most salient shortcomings of the instrument relate to the Social, Environmental and Religion/Spirituality/Personal Beliefs domains of the instrument. Themes not captured by the instrument include family responsibilities, disease disclosure, exclusion from common resources, basic needs, adequate food, and job opportunities. In addition, several of the tool's facets such as dependence on medicine seem less relevant. Also, the role of religion is more complex than captured in WHOQOL-HIV. We found that the tool is based on an individualist focus, which tends to overlook the social context of the patient. CONCLUSION: We conclude that the conceptual equivalence of WHOQOL-HIV is only partially attained for use in Ethiopia. The findings from this qualitative study are used in the further process of developing and validating a QoL instrument for use in Ethiopia.