Multiple sclerosis (MS) is a human neurological disease for which no clinically useful marker has been identified in blood. This study examined α 2-macroglobulin ( α 2M) from the plasma of six patients with chronic-progressive MS and six with relapsing-remitting disease. The α 2M trypsin-binding activity in the plasma from both groups of patients did not differ from normal controls. However, after column isoelectric focusing, consistently less α 2M activity was recovered from the MS samples: those from the chronic-progressive and relapsing-remitting disease groups were an average of 43% and 68%, respectively, of controls. The number and isoelectric point (p I) values of the isoforms of the α 2M from patients with chronicprogressive disease were similar to controls. The average p I of the major form for both groups was 6.6. By contrast, the average p I of the major form from the patients with relapsing-remitting MS was significantly elevated to 7.1, and this group displayed a significantly higher percentage of total recovered activity above pH 7.0. In eleven of the twelve cases examined, the p I of the major form of α 2M correctly correlated with the clinical status of the patient. The original clinical diagnosis of the patients was reassessed by a 9-year retrospective interview which verified that 9 of the 10 patients in the follow-up group retained their original clinical diagnosis. These studies demonstrate differential isoform profiles of native α 2M from MS patients with progressive versus remitting disease which may be useful in subclassifying MS patients.