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Fifty-four patients with chronic progressive multiple sclerosis received prednisone plus oral low-dose cyclophosphamide and either true plasmapheresis (PP) or "sham" PP weekly for 20 weeks in a double-blind controlled study. Immunosuppressive drug therapy alone (sham PP group, n = 29) was associated with improvement (greater than or equal to one step in Kurtzke Disability Status Scale [DSS]; mean change of 1.5) in 8 and stabilization of MS in 18 patients, with this status sustained in 23 patients at follow-up, 11 months after entry. In contrast, 14 of 26 patients who received "true" PP improved (greater than or equal to one step in DSS; mean change of 2.6), and 11 more were stable, with these changes sustained in 23 of 26 patients at follow-up. These differences, overall, between the PP and sham PP groups were significant at p less than 0.007.