We examined the proteinase inhibitor alpha2-macroglobulin (alpha2M) in plasma from patients with multiple sclerosis (MS); a neurological disease of the central nervous system. The plasma concentrations of native and transformed alpha2M were measured in 90 patients with clinically definite MS, 73 with relapsing-remitting and 17 with secondary progressive MS, and 132 healthy individuals. Significantly lower concentrations of native alpha2M and significantly higher concentrations of transformed alpha2M were found in MS patients. A significant correlation between the concentrations of native and transformed alpha2M was found. The fraction of transformed to total alpha2M in the MS patients was 36% higher than in the healthy individuals. The results suggest an important involvement of alpha2M in regulation of increased proteolytic activity occurring in MS disease.