Primary central nervous system lymphoma (PCNSL) is a rare and highly malignant tumor with increasing incidence. Survival has improved with the use of nonsurgical treatment modalities, of which methotrexate (MTX)-based intrathecal chemotherapy has been an important option. Here, we describe devastating complications in three patients with diffuse large B-cell lymphomas. After intrathecal MTX therapy two patients died secondary to fulminant brain edema. A third patient developed severe dementia, gait disturbance and urinary incontinence due to leukencephalopathy. Since bulky disease was present in all three patients, CSF flow may have been impaired. This might have exposed adjacent tissue to prolonged toxic drug concentrations. Regarding the severe complications seen in these patients, it is useful to consider high-dose intravenous MTX treatment only in periventricular PCNSL.