BackgroundHuman rights approaches now dominate the HIV prevention landscape across sub-Saharan Africa, yet little is known about how they are viewed by the populations they are designed to serve. Health interventions are most effective when they resonate with the worldviews and interests of target groups. This study examined local Zambian understandings of human rights approaches to HIV-prevention among three highly HIV-vulnerable groups: women, youth, and men-who-have-sex-with-men (MSM).MethodsFocus groups included 23 women, youth, and MSM who had participated in activities organized by local non-governmental organizations (NGOs) using rights-based approaches, and interviews included 10 Zambian employees of these NGOs. Topics included participants’ experiences and views of the utility of these activities. Thematic analysis mapped out diverse ways participants viewed the concept of human rights in relation to HIV-prevention.ResultsWhilst NGO workers noted the need for human rights programs to address the complex drivers of the HIV epidemic, they struggled to tailor them to the Zambian context due to donor stipulations. Women program beneficiaries noted that the concept of human rights helped challenge harmful sexual practices and domestic abuse, and youth described rights-based approaches as more participatory than previous HIV-prevention efforts. However, they criticized the approach for conflicting with traditional values such as respect for elders and ‘harmonious’ marital relationships. They also critiqued it for threatening the social structures and relationships that they relied on for material survival, and for failing to address issues like poverty and unemployment. In contrast, MSM embraced the rights approach, despite being critical of its overly confrontational implementation. ConclusionsA rights-based approach seeks to tackle the symbolic drivers of HIV—its undeniable roots in cultural and religious systems of discrimination. Yet, it fails to resonate with youth and women’s own understandings of their needs and priorities due to its neglect of material drivers of HIV such as poverty and unemployment. MSM, who suffer extreme stigma and discrimination, have less to lose and much to gain from an approach that challenges inequitable social systems. Developing effective HIV-prevention strategies requires careful dialogue with vulnerable groups and greater flexibility for context-specific implementation rather than a one-size-fits-all conceptualization of human rights.