The expression of tissue-type plasminogen activator (t-PA) and a number of metalloproteases as well as plasminogen activator inhibitor-1 (PAI-1) and tissue inhibitor of metalloproteases-1 (TIMP-1) was analyzed in the central nervous system (CNS) of normal control and multiple sclerosis (MS) cases by immunohistopathology. The expression of t-PA was detectable only in the blood vessel matrix in control white matter, but positive infiltrating mononuclear cells were also observed in MS white matter and primary lesions. In active plaques this pattern converted to strong positivity of foamy macrophages in areas of demyelination, declining in chronic lesions. In general PAI-1 expression paralleled that of t-PA. Gelatinase A and B were detected predominantly in astrocytes and microglia throughout normal control white matter, with additional positive mononuclear cells in perivascular cuffs in MS white matter. In the demyelinating lesion there is widespread prominent expression of gelatinase B in reactive astrocytes and macrophages, which persists in astrocytes in the chronic lesion. TIMP-1 was also present in the vessel matrix and in lesional macrophages. These observations on the coexpression of enzymes and inhibitors of the matrix degrading cascade in CNS tissue pinpoint t-PA, a rate-limiting enzyme, and gelatinase B as therapeutic targets in MS.