Purpose: The current study examined the relationships between health-related quality of life (HRQOL) and social determinants of health (SDH), which are the individual and structural factors that contribute to health outcomes. Method: A hierarchical general linear model was used to assess the sequential effect of the SDH on the scores of the Short Form-12 among people living with HIV. Results: Results show that many psychosocial, medical, demographic, financial, and vocational factors are significant predictors of HRQOL. Conclusions: Gaining a deeper understanding of the impact of SDH on HRQOL is critical for rehabilitation counselors to develop effective assessments and interventions.