All chemotherapeutic agents have the potential to induce hypersensitivity reactions and the repeated administration of such drugs during a cancer treatment enhances specific sensitization. Epipodophyllotoxins (etoposide and teniposide) are commonly used to treat lung, testicular, central nervous system and hematologic cancers. Hypersensitivity reactions to epipodophyllotoxins are not the most common but they have been reported. We present a case of an eight-year-old male patient, diagnosed with high risk acute lymphoblastic leukemia who received treatment with etoposide among other drugs (St. Jude XIIIB). During the first course of treatment he needed premedication to etoposide administration because of mild hypersensitivity reactions. At the beginning of a second treatment the patient presented two severe hypersensitivity reactions (acute urticaria, angioedema and hypotension) despite the use of premedication and slow infusion. We initiated a twelve steps desensitization protocol for etoposide with success in the second round allowing the administration of further doses in an ambulatory unit without hypersensitivity reactions.