Introduction Temozolomide is an oral alkylating agent used as first line treatment of glioblastoma multiforme (GBM). It has also been used in the treatment of certain solid tumors such as metastatic melanoma. Commonly reported adverse effects include nausea and vomiting, constipation, headache, fatigue and myelosuppression. Cutaneous hypersensitivity reactions are rare and include an urticarial hypersensitivity reaction, alopecia, and Stevens–Johnson syndrome. To our knowledge, there are minimal reports of temozolomide-induced DRESS syndrome. Case Report We present a 54-year-old man with glioblastoma multiforme who presented with a fever, diarrhea and progressively worsening rash 6 weeks after starting temozolomide. Management & Outcome The patient was diagnosed recurrent DRESS syndrome and restarted on a gradual prednisone taper with resolution over the following weeks. Unfortunately, the patient was unable to be followed long-term due to relocation to a different state. Discussion To our knowledge, there are minimal reports of temozolomide-induced DRESS syndrome. The diagnosis can be life-threatening, which makes management of patients with GBM and no alternative treatment option challenging. The use of de-sensitization therapy to temozolomide has been proposed for the management of severe adverse cutaneous reactions.