Methotrexate is a dihydrofolate reductase inhibitor with application both as a chemotherapeutic agent and as a disease-modifying antirheumatic drug. Although its ability to inhibit cellular proliferation is a desired effect in its role as an antineoplastic agent, this property may also hinder normal physiologic regeneration of the nasal epithelium. This effect may predispose patients to septal cartilage ischemia, necrosis and, eventually, perforation. We report 2 cases of septal perforations in the setting of prolonged methotrexate use and present a literature review. Patient 1 is an 8-year-old boy with juvenile rheumatoid arthritis managed with weekly methotrexate who developed a 4-mm septal perforation with an unremarkable biopsy. This was closed with a mucosal advancement flap without incident. Patient 2 is an 11-year-old boy with non-Hodgkin lymphoma treated with methotrexate. His examination was significant for a large perforation of the dorsocaudal septum. A biopsy was negative for malignancy in this patient. Repair has been deferred-initially for chemotherapy and currently for treatment relapse. We hypothesize that prolonged use of methotrexate alters the balance between physiologic desquamation and epithelial regeneration. This imbalance may promote septal ischemia and predispose patients to the development of septal perforations.