Twenty-six patients, who received plasmapheresis (PP) either alone or synchronized with cyclophosphamide (IV-CYC/PP), are retrospectively reviewed from Medline searches and personal experience from 1976 to 2002. Patients with central nervous system neuropsychiatric systemic lupus erythematosus (CNS-NPSLE) were evaluated according to the American College of Rheumatology (ACR) case definitions of 1999. Eleven of the patients were under the age of 21 years (range 7-21 years), highlighting the need for an aggressive treatment option for young patients who are refractory to other treatments. After treatment with PP or IV-CYC/PP, 74% of patients improved, 13% stabilized, and 13% progressed. Major side-effects occurred from central line placement rather than immunomodulation from PP itself Step-down therapies are needed to supplement IV-CYC/PP once improvement has reached a plateau. Newer combinations of PP and intravenous immunoglobulin (IVIg), human stem cell transplant (HSCT) and rituximab (RTX) should be considered in the future. In the absence of randomized controlled trials (RCT), experienced clinicians must weigh risk, benefit, and cost profiles in considering the treatment of severe CNS-NPSLE with PP.