Background <p>Antiretroviral therapy has increased life expectancy of people living with HIV, though estimates of quality of life remain consistently lower than that of the general population. Research on determinants of health-related quality of life among people living with HIV has predominantly focused on clinical factors, with limited attention to upstream structural determinants, or the economic, political, and social systems shaping resource distribution and health outcomes. Moreover, structural and social determinants are frequently conflated in the literature, challenging both conceptual clarity and intervention design. A comprehensive synthesis leveraging a conceptual framework can support improved characterization of which structural factors are most strongly associated with health-related quality of life, distinguish structural from social determinants, and inform policy and programmatic priorities for improving the health and wellbeing for people living with HIV.</p> Methods <p>We systematically searched PubMed, Embase, CINAHL, PsycINFO, PAIS, Sociological Abstracts, and Scopus from database inception to February 2026. Eligible studies will quantitatively examine associations between structural determinants (including policy and legal environment, culture, social class, socioeconomic position, stigma and discrimination, built environment, and material living conditions) and health-related quality of life measured using validated instruments among people living with HIV. Two reviewers will independently screen studies, extract data, and assess risk of bias using Joanna Briggs Institute critical appraisal tools. Random-effects meta-analysis will pool effect estimates where sufficient homogeneity exists. Subgroup analyses will examine variation by geographic region, gender, race, and structural determinant category.</p> Discussion <p>This review will systematically synthesize evidence on structural determinants of health-related quality of life among people living with HIV. Findings will identify modifiable upstream factors associated with quality of life, informing prioritization of structural interventions alongside biomedical approaches to HIV care. The review will also map evidence gaps, highlighting under-explored structural determinants and populations to guide research. By contributing to conceptual clarity in a field where structural and social determinants are frequently conflated, this review will provide a framework for more precise measurement and intervention design in future studies.</p> Systematic review registration <p>PROSPERO CRD420261373190</p>