Health-related quality of life in adolescents and ethnic and cultural differences are not well characterized. We used the Quality of Life Questionnaire for Adolescents (QOLQA) to examine ethnic differences in reported QOL scores among Chinese, Malay and Indian ethnicities in Singapore. The 70-item QOLQA measuring five QOL domains (physical, psychological, independence, social and environmental) was administered to a random sample of 1363 school-children aged 10-15 years, representative of the ethnic composition of Singapore adolescents (Chinese 72%, Malays 20% and Indians 8%). Indians reported the highest overall QOL (mean 3.71 +/- SD 0.54) compared to Chinese (3.59 +/- 0.43), p < 0.05, and Malays (3.58 +/- 0.44), p < 0.05. In particular, Indians had significantly higher psychological QOL scores (3.73 +/- 0.61) compared to Chinese (3.55 +/- 0.54), p < 0.01. On the other hand, Chinese scored highest on physical and independence domains (3.97 +/- 0.54), p < 0.01 compared to Malays (3.82 +/- 0.55). There were no statistically significant gender differences in QOL scores. QOL declined significantly from age 10 to 15 for overall score, psychological, physical (p < 0.01) and environmental (p < 0.05). Lower socio-economic status and the self-report of a significant health problem were significantly associated with lower overall QOL and most domains. These ethnic differences persisted after adjusting for differences in socio-economic and health status. Psychometric properties and known group construct validity appeared to be similar across different ethnic groups, but compared to Chinese (r = 0.39) or Malays (r = 0.39), Indians showed a higher correlation of psychological scores with physical score (r = 0.59) and with other domain scores. Significant ethnic differences in reported adolescent quality of life among Chinese, Malays and Indians in Singapore that are independent of socioeconomic and health status suggest important cultural differences.