Both cranial radiation therapy (RT) and high-dose systemic methotrexate (MTX) are used to treat intracranial neoplasmas, but both may cause neurologic damage. MTX may be less neurotoxic if given before rather than after radiotherapy. We cared for a 5-year-old girl with a pineocytoma who had progressive brain stem dysfunction 4 months after MTX therapy, followed by local radiation therapy. CT studies were consistent with radiation necrosis that was confirmed at autopsy. MTX used in conjunction with cranial irradiation can result in severe neurotoxicity, even if the drug is given first.