Objective To compare the health related quality of life (HRQOL) of children with chronic kidney disease (CKD) to healthy children; to evaluate the association between CKD severity and HRQOL; to identity demographic, socioeconomic and health-status variables associated with impairment in HRQOL in children with mild to moderate CKD. Patients and Methods This is a cross-sectional assessment of HRQOL in children aged 2-16 with mild to moderate CKD using the Varni PedsQL™. Overall HRQOL and PedsQL domain means for parents and youth were compared to previously published norms using independent sample t-tests. Study participants were categorized according to kidney disease stage (measured by iohexol based glomerular filtration rate, iGFR) and group differences in HRQOL were evaluated using ANOVA and Cuzick trend tests. The association between hypothesized predictors of HRQOL and PedsQL scores was evaluated with linear and logistic regression analyses. Results The study sample was comprised of 402 participants (Mean age =11 yrs, 60% male, 70% Caucasian, 40% anemic, median iGFR=42.5 ml/min/1.73m2, median CKD duration= 7 yrs). Youth with CKD had significantly lower physical, school, emotional and social domain scores than healthy youth (p<.001). IGFR was not associated with HRQOL. Longer disease duration and older age was associated with higher PedsQL scores in the domains of physical, emotional and social functioning (p<.05). Older age was associated with lower school functioning domain scores (p<.05). Maternal education ≥16 years was associated with higher PedsQL scores in the domains of physical, school, and social functioning (p<.05). Short stature was associated with lower scores in the physical functioning domain (p<.05). Conclusions Children with mild to moderate CKD, in comparison to healthy children, report poorer overall HRQOL as well as poorer physical, school, emotional and social functioning. Early intervention to improve linear growth and to address school functioning difficulties is recommended.