Health-related quality of life (HRQOL) assessment has emerged as a vital health outcome measure in clinical trials, healthcare services and evaluation, and population health outcomes research. Reliability, validity, and parent-child agreement of the PedsQL™ 4.0 Generic Core Scales were examined using child self-report and parent proxy-report age subgroup data on over 8,000 children ages 5-16 years from the PedsQL 4.0 Generic Core Scales DatabaseSM. The PedsQL™ 4.0 Generic Core Scales demonstrated good internal consistency reliability for children as young as 5 years; healthy children across the age subgroups demonstrated a statistically significant difference in HRQOL (better HRQOL) than children with a known chronic health condition. Confirmatory factor analysis demonstrated that a 5-factor model fit almost identically across the age subgroups, providing further evidence that children as young as 5 years are reliable and valid self-reporters of their HRQOL. Parent-child agreement was in the moderate-to-good range, with parents reporting significantly higher PedsQL™ 4.0 scores across the age subgroups. In conclusion, the analyses support the reliability and validity of child self-report in children as young as 5 years old.