Lymphopenia is a common consequence of therapy for malignant glioma. Current standard therapy includes corticosteroids, temozolomide and radiation therapy, all of which are toxic to lymphocytes. The resulting immunosuppression has serious clinical consequences. Decreased lymphocyte counts can result in opportunistic infections, decreased efficacy of immunotherapy and reduced overall survival. The exact mechanisms underlying the association between decreased survival and lymphopenia in malignant glioma patients are unclear. However, as lymphocytes are key effector cells in the immune response to cancer, it is likely that depleting their numbers renders the immune system less effective at eliminating malignant cells. Currently, no strategies exist for the prevention or reversal of treatment-related immunosuppression in malignant glioma patients, although there are several promising theoretical approaches. This article reviews the current state of knowledge regarding the severity, etiology and possible consequences of treatment-related lymphopenia in patients with malignant glioma.