Background Studies have shown that women aging with HIV have significantly lower health-related quality of life (HRQoL) compared to women without HIV. However, no studies have examined this issue in Latin America and the Caribbean. We aimed to explore HRQoL measured by the 36-Item Short Form Health Survey (SF-36) among women aging with and without HIV in Peru. Materials and methods We conducted a cross-sectional study at a large HIV-clinic in Peru. Outcomes of the SF-36 were evaluated, exploring the relationship between physical activity (International Physical Activity Questionnaire), sociodemographic factors (ethnicity, alcohol/tobacco use, age, BMI) and clinical data (AIDS progression, treatment duration, CD4+ cell count and viral load, years since HIV diagnosis) with HRQoL using regression analysis. Statistical significance was set with a two-tailed p-value <0.05. Results We enrolled 427 women (175 HIV-infected) with mean age of 54±8 years. From the SF-36 individual domains: physical functioning, role limitations due to physical and emotional health, and emotional wellbeing were significantly lower for HIV-infected women. Summary component scores were lower for the HIV-subset for both physical (45.8 vs 47.3) and mental (45.1 vs 45.8) components, although they did not achieve statistical significance. Regression analysis of the HIV-infected women revealed that the physical component score was significantly associated with physical activity, ethnicity, and chronic comorbidities while the mental component was significantly associated with physical activity, employment, and CD4 + cell count. Conclusion In our study, HIV-infected women scored lower in both physical and mental component scores. Important determinants for each component included CD4+ cell count as an assessment of HIV severity for the mental component, and ethnicity, reflecting socio-cultural factors, for the physical component. These results reveal the importance of a holistic approach to addressing HRQoL in this population. Better understanding of these factors will help shape future policies and interventions to improve HRQoL of women aging with HIV.