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Purpose: The purpose of this study was to evaluate the reliability and validity of the Thai Quality of Life in Children (ThQLC) and compare it with the Pediatric Quality of Life Inventory (PedsQL™ 4.0) in a sample of children receiving long-term HIV care in Thailand. Methods: The ThQLC and the PedsQL™ 4.0 were administered to 292 children with HIV infection aged 8-16 years. Clinical parameters such as the current viral load, CD4 percent, and clinical staging were obtained by medical record review. Results: Three out of five ThQLC scales and three out of four PedsQL™ 4.0 scales had acceptable internal consistency reliability (i.e., Cronbach's alpha >0.70). Cronbach's alpha values of each scale ranged from 0.52 to 0.75 and 0.57 to 0.75 for the ThQLC and the PedsQL™ 4.0, respectively. Corresponding scales (physical functioning, emotional well-being, social functioning, and school functioning) of the ThQLC and the PedsQL™ 4.0 correlated substantially with one another (r = 0.47, 0.67, 0.59 and 0.56, respectively). Both ThQLC and PedsQL™ 4.0 overall scores significantly correlated with the child's self-rated severity of the illness (r = -0.23 for the ThQLC and -0.28 for the PedsQL™ 4.0) and the caregiver's rated overall quality of life (r = 0.07 for the ThQLC and 0.13 for the PedsQL™ 4.0). The overall score of the ThQLC correlated with clinical and immunologic categories of the United State-Centers for Disease Control and Prevention (US-CDC) classification system (r = -0.12), while the overall score of the PedsQL™ 4.0 significantly correlated with the number of disability days (r = -0.12) and CD4 percent (r = -0.15). However, the overall score from both instruments were not significantly different by clinical stages of HIV disease. A multitrait-multimethod analysis results demonstrated that the average convergent validity and off-diagonal correlations were 0.58 and 0.45, respectively. Discriminant validity was partially supported with 62% of validity diagonal correlations exceeding correlations between different domains (discriminant validity successes). The Hays-Hayashi MTMM quality index was 0.61. Multivariate regression analysis revealed that the ThQLC physical functioning scale provided unique information in predicting child self-rated severity of the illness and overall quality of life beyond that explained by the PedsQL™ 4.0 in Thai children with HIV infection. Conclusions: We found evidence in support of the reliability and validity of the ThQLC and the PedsQL™ 4.0 for measuring the health-related quality of life of Thai children with HIV infection. © 2010 The Author(s).