Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) are among the main causes of morbidity and mortality attributed to lupus activity. Conventional NPSLE treatment combines CS and immunosuppressants, but some symptoms do not respond. We retrospectively evaluated the adjunction of plasma exchanges (PE) to treat 13 NPSLE flares occurring in 10 patients (mean age, 30 years) between 1989 and 2002. NP manifestations were the first SLE symptoms for seven patients, with a mean of 3.2 NP manifestations/flare. All patients received CS and cyclophosphamide pulses. A mean of 15 PE/flare were performed. All patients improved within a mean of 3 (median: 2.5; range: 1.5-8) weeks thereafter. Complete remissions of 7/13 flares were obtained within a mean of 7 (median: 4; range: 2-22) weeks. Partial remissions were achieved for the remaining six flares, characterized by new NP manifestations during three and insufficient control of the others. Other SLE manifestations regressed for all patients with the mean European consensus lupus activity measurement score declining from pretreatment 6.9 to 1.2. A regimen combining CS, cyclophosphamide and PE is effective against severe NPSLE, with acceptable toxicity.