Both 2-mercaptoethane sulfonate sodium (mesna) and amifostine's active metabolite WR-1065 are thiol-based cytoprotective agents that are critical components of high-dose chemotherapy regimens used to treat various cancers in both adults and children. This case report describes a patient with a supratentorial primitive neuroectodermal tumor who developed severe drug reactions to both mesna and amifostine/WR-1065, suggesting that the thiol component of these agents triggered the adverse reactions. This report highlights the clinical presentation of drug-induced hypersensitivity syndrome in the context of pediatric oncology and the supportive care measures that, if implemented rapidly, may diminish the reaction severity and allow successful completion of chemotherapy.