Purpose/Objectives: To examine the influence of the proposed symptom cluster of fatigue, nausea and vomiting, and sleep disturbances on clinical outcomes defined as behavior changes, depression, and performance status in children and adolescents before and after receiving cisplatin, doxorubicin, or ifosfamide chemotherapy. Design: A prospective, descriptive, within-group, before and-after-chemotherapy design was used. Setting: Two major childhood cancer treatment hospitals in the United States. Sample: 67 patients aged 7-18 years who were receiving chemotherapy courses of cisplatin, doxorubicin, or ifosfamide. Methods: Fatigue, depression, behavior, and performance assessments were completed on the first day of cisplatin, doxorubicin, or ifosfamide therapy and one week later. Patients wore a wrist actigraph on the nondominant hand during the course of therapy and for 48 hours after discharge from the hospital. Nausea and vomiting were measured every 24 hours during the course of therapy and for 48 hours after discharge. A linear mixed model was used to evaluate the influence of the symptom cluster. Regression analysis was used to examine the associations between performance status and the symptom cluster. Principal component analysis with varimax rotation was used to produce the correlation of sleep symptoms. Main Research Variables: Fatigue, nausea and vomiting, sleep disturbances, behavior, depression, and performance. Findings: Adolescents with the cluster of increased fatigue and sleep disturbances experienced more depressive symptoms and behavior changes. Children with higher levels of fatigue had increased depressive symptoms. The more fatigue parents perceived in their children or adolescents, the more behavior and emotional difficulties were reported. Conclusions: Fatigue, sleep disturbance, and nausea and vomiting, when clustered, impacted depressive symptoms and behavior changes in adolescents after chemotherapy. In children, fatigue alone impacted depressive symptoms and behavior changes. Implications for Nursing: Symptom clusters can have a significant impact on children's and adolescents' quality of life during cancer treatment. Early recognition and intervention for these symptoms are an important nursing role.