We studied the relationship between plasma α<sub>2</sub>-macroglobulin (α<sub>2</sub>M) and depressed cell-mediated immunity in idiopathic nephrotic syndrome (INS). Plasma α<sub>2</sub>M concentrations (μmol/l) were increased during relapses of INS; however, the proteinase inhibitory activity, measured using bacterial thermo-lysin, was significantly decreased when calculated per 1 mol of α<sub>2</sub>M, implying a reduced proteinase-inhibiting capacity of α<sub>2</sub>M. The decreased proteinase-inhibiting capacity of α<sub>2</sub>M was associated with the inhibitory activity of plasma on normal lymphocyte blastogenesis. Purified α<sub>2</sub>M, when complexed with chymotrypsin, intensively inhibited normal lymphocyte blastogenesis induced by concanavalin A, as compared with the free form of α<sub>2</sub>M. From these results it is suggested that, although the amount of α<sub>2</sub>M protein has increased in the plasma of INS patients during relapse, its binding capacity to proteinases has relatively decreased. The results of this study may provide speculation for both the well-known high plasma α<sub>2</sub>M concentrations and the immunodepres-sion, both of which have been observed in INS patients in the past few decades.