On the Fourth Intergroup Rhabdomyosarcoma study, older children experienced excessive neurotoxicity, whereas younger children had increased myelosuppression. The purpose of this study was to determine whether the same pattern of toxicity was seen on the successor study when use of growth factor was required and dosing of chemotherapy was different by performing a retrospective cohort analysis on patients treated on Children's Oncology Group protocol D9803. Toxicity data were analyzed by stratifying children into 4 age groups. The frequency of grade 3/4 neurotoxicity, myelosuppression, infection, and mucositis was predicted for each age group. The cumulative doses of vincristine and cyclophosphamide administered were measured as percent of protocol-prescribed dose. Adolescents (aged 15+) were more likely to experience neurotoxicity compared with younger patients (odds ratio, 3.6; P<0.0001). There was no difference in myelosuppression, infection, or mucositis. The mean percent protocol-prescribed doses administered for vincristine and cyclophosphamide did not differ much by age group. Adolescents experienced more neurotoxicity with vincristine compared with younger patients. No differences in other toxicities were observed between age groups. As adolescents received at least 85% of protocol-prescribed doses of vincristine, it is difficult to attribute the poorer survival in this age group to inadequate protocol-delivered therapy.