Children with cancer experience a myriad of disease or treatment related symptoms. Little is known about the multiple dimensions of these symptoms, how these dimensions change during treatment, and the relationship between symptoms and health related quality of life (HRQOL). The purposes of this study, in a sample of children who underwent myelosuppressive chemotherapy were to: describe changes in symptom occurrence and severity during a course of chemotherapy. In addition, these children’s scores on a generic measure of HRQOL were compared to a normative sample of healthy children and relationships between demographic, clinical, and symptom characteristics and generic and disease-specific dimensions of HRQOL were examined in the children with cancer. Children completed the Memorial Symptom Assessment Scale (MSAS), the PedsQL Generic and Cancer Modules, and the Karnofsky Performance Status (KPS) at the start of chemotherapy (T1) and weekly for the next two weeks (T2 and T3). Patients (n=66), were predominantly male (51.5%), minority (62.1%), and 14.9 years of age. The mean number of symptoms per patient was 10.6 at T1, 10.7 at T2, and 8.4 at T3. Using multilevel logistic regression, fatigue, sadness, irritability, worrying, weight loss, and sweating showed a decreasing linear trend. Significant quadratic patterns of change were found for feeling drowsy, nausea, and vomiting. Using multilevel negative binomial regression, no significant differences, over time were found in any of the MSAS symptom severity scores. Compared to the normative sample, children with cancer reported significantly lower total and subscale scores except for emotional and social functioning. No significant differences were found between any demographic characteristics and any total or subscale scores on the generic or disease specific measures of HRQOL. Lower KPS scores were associated with poorer generic and disease specific HRQOL scores. A higher number of symptoms and higher symptom distress scores were associated with poorer generic and disease specific HRQOL scores. Children experienced a high number of symptoms at the initiation of a chemotherapy cycle that persisted over the subsequent two weeks. Among the demographic, clinical, and symptom characteristics studied, poorer functional status and higher symptom burden were associated with significant decreases in HRQOL