Primary central nervous system lymphoma (PCNSL) is a rare disease that is managed differently from other primary brain tumors and other types of systemic lymphomas. The use of high-dose methotrexate (HD-MTX) has improved survival rates. This article describes the experience of a patient treated with HD-MTX and outlines the essential aspects of care for the bedside practitioner. An understanding of the diagnostic workup and principles of treatment can minimize complications and maximize patient function as nurses care for the unique physical and emotional needs of this population.