A 60-year-old woman with no previous history of chronic disease or malignancy presented with intense back and left leg pain and sleep disturbances. The patient had been treated unsuccessfully for the past 6 months with analgetics. Magnetic resonance imaging showed a soft tissue tumor in the L5-S1 region that involved the spinal canal, and a pathohistological analysis of the tumor specimen confirmed the presence of non-Hodgkin, diffuse large B cell lymphoma. After the diagnosis was confirmed, malaise, nausea, and vomiting developed. Multislice computed tomography of the endocranium showed focal infiltration of the hypothalamus and lateral ventricle; dissemination of a systemic lymphoma was excluded. Therapy was initiated as per the De Angelis protocol. After intravenous and intrathecal administration of metotrexate, the patient developed signs of central diabetes insipidus, which responded to therapy with an antidiuretic hormone analog. Despite the obvious infiltration of the hypothalamus, we cannot exclude an idiosyncratic effect of methotrexate on the central diabetes insipidus.