Intracranial anaplastic ependymomas are a very rare entity within the group of adult CNS neoplasms. Thus, no standard adjuvant therapy after surgical resection has been defined so far. External radiotherapy is commonly administered, but the role of chemotherapy is still unclear in malignant ependymomas. The case of a 25-year-old female patient with multifocal recurrence of a supratentorial malignant ependymoma administered temozolomide as second-line therapy is reported. Currently, 5 months after initiation of temozolomide treatment, there is no evidence of radiographic progression. Temozolomide could constitute a promising approach to supratentorial recurrent and multifocal anaplastic ependymoma of adults.