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Illness uncertainty is prevalent in children with cancer and has been associated with increased psychological distress. The relationship between illness uncertainty and quality of life in pediatric cancer patients remains unclear. The aim of the present study was to examine illness uncertainty as a predictor of health-related quality of life in children diagnosed with cancer. It was hypothesized that child-reported illness uncertainty would be negatively associated with child health-related quality of life.Children aged 8 to 18 years old and receiving treatment for cancer were recruited to participate in this study. One hundred twenty children and their parent(s) completed measures of illness uncertainty, pain, anxiety, and quality of life during a routine visit to the Cancer Center at Children’s Hospital of Orange County.Illness uncertainty was significantly associated with child age (P=0.02), overall health-related (P<0.001) and cancer-related (P<0.001) quality of life, but not with treatment status (on/off chemotherapy) or demographic variables including sex and household income. Regression analyses statistically controlling for age, anxiety, and pain revealed that illness uncertainty significantly predicted child-reported cancer-related and health-related quality of life (P<0.01) as well as parent-reported cancer-specific quality of life (P<0.01).Illness uncertainty is prevalent and associated with lower quality of life in children diagnosed with cancer. Improved communication with children regarding disease state, treatment expectations, and prognosis may alleviate uncertainty and improve functioning in this vulnerable patient population.