The aim of this report is to describe the management of scalp toxic epidermal necrolysis (TEN) and cranial osteomyelitis complicating malignant glioma therapy. A 21-year-old man developed TEN while being radiated and receiving antineoplastic and anticonvulsant therapies for a malignant intracranial glioma. The strategy used to manage the above situation included withdrawal of the medications causing TEN, meticulous dermatological wound care, resection of residual glioma, debridement of scalp and bone, and reconstruction of the scalp and calvarial defect with a myocutaneous vascularized free flap. The scalp wounds have healed completely in a cosmetically acceptable fashion and the patient remains free of tumor recurrence approximately 18 months after surgery, having completed a course of systemic chemotherapy. TEN may complicate the use of anticonvulsant and antineoplastic medications in malignant glioma patients. Withdrawal of the offending agent and immune suppressant medications, skin care and infection control, tumor resection to diminish steroid use, and reconstruction of scalp and calvarial defects with a vascularized myocutaneous flap facilitate wound healing and permit resumption of antineoplastic therapies.