BACKGROUND: HIV/AIDS remains a major public health concern in Vietnam. While advancements in antiretroviral therapy (ART) have significantly enhanced survival rates and transformed HIV into a manageable chronic condition, the health-related quality of life (HRQL) of people living with HIV/AIDS (PLHA) often falls short of optimal levels. PURPOSE: This study aims to evaluate the HRQL of HIV/AIDS outpatients at the Hospital for Tropical Diseases in Vietnam and identify key factors impacting their well-being. METHODS: A cross-sectional study was conducted among 328 PLHA receiving care at the Hospital for Tropical Diseases between March 2023 to March 2024. Data was collected using the World Health Organization Quality of Life-HIV Brief Version (WHOQOL-HIV BREF) instrument and included socio-demographic, clinical, and treatment-related variables. Descriptive statistics were utilized to summarize the data. Inferential statistical analyses, including independent -test, one-way ANOVA, Kruskal-Wallis tests, and linear regression, were performed to evaluate the relationships between HRQL domains and participant characteristics. Statistical significance was set at p < 0.05. RESULTS: The mean overall quality of life score was 14.6 ± 2.2. The highest domain scores were observed in spirituality (15.1 ± 3.5) and environment (15.1 ± 2.9), while the lowest was in the physical domain (14.1 ± 2.0). Significant determinants of overall quality of life included age, marital status, employment type, income, financial difficulties, chronic diseases, and CD4 counts (all p < 0.05). CONCLUSION: This study highlights the multifaceted challenges affecting the quality of life of PLHA, emphasizing the need for a holistic care approach. Being married, having stable employment, and having higher CD4 counts were associated with better quality of life, whereas older age, unstable income, financial struggles, and comorbidities were linked to poorer outcomes. Interventions addressing these determinants, including chronic disease management, social and mental health support are crucial for enhancing overall well-being.