Given the prolonged survival of HIV-infected individuals as a result of widespread availability of treatment, health-related quality of life (HRQOL) becomes a relevant endpoint for assessing the impacts of HIV interventions. We examined the reliability and validity of the World Health Organization Quality of Life in HIV-infected Persons instrument (WHOQOL-HIV-BREF) using data from 329 HIV-infected Thai patients who received outpatient care at seven public hospitals. Our findings revealed acceptable reliability, construct validity, and convergent validity of the WHOQOL-HIV-BREF. No significant difference in HRQOL was found between groups with different CD4+ T cell counts. Conversely, the subgroup with a history of opportunistic infection appeared to have a higher HRQOL compared to those in the latency stage. Challenges to the interpretation of the questions related to culture are discussed. In conclusion, the WHOQOL-HIV-BREF can be added to the limited list of instruments for comprehensive outcome evaluation of HIV interventions in Thailand.