In-depth interviews and focus group discussions were conducted to inform the development of an instrument to measure the health-related quality of life of children living with HIV. The QOL-CHAI instrument consists of four generic core scales of the "Pediatric Quality of Life Inventory" and two HIV-targeted scales—"symptoms" and "discrimination." A piloting exercise involving groups of children living with HIV and HIV-negative children born to HIV-infected parents provided evidence for the acceptable psychometric properties and usability of the instrument. It is expected that the QOL-CHAI can serve well as a brief, standardized, and culturally appropriate instrument for assessing health-related quality of life of Indian children living with HIV.