Abnormal fat deposition in the epidural space or spinal epidural lipomatosis (SEL) due to corticosteroid treatment or obesity may cause obstruction to cerebrospinal fluid flow. Little is known about SEL in patients with hematologic malignancies who require frequent lumbar punctures and corticosteroid treatment that places them at risk. Records and radiologic images of patients with SEL and leukemia or non-Hodgkin lymphoma (NHL) treated at a single institution from 1999-2009 were reviewed. Risk factors were compared with 405 control patients with leukemia. Fourteen patients with leukemia or NHL were diagnosed with SEL. The majority of patients underwent diagnostic imaging after unsuccessful lumbar punctures within 1 month of their primary diagnosis. Prior to SEL diagnosis, all patients received systemic and/or intrathecal corticosteroids. SEL diagnosis led to modification of intrathecal administration in eight patients, including Ommaya reservoir placement in four patients. All patients completed protocol-specified chemotherapy without neurologic symptoms or surgical intervention. Risk factors for developing SEL include older age and high body mass index. Investigation for SEL in leukemia or lymphoma patients with difficult lumbar punctures is warranted. Placement of an Ommaya reservoir may facilitate safe CNS-directed therapy in severely affected patients.