Because of its close sequence homology to immunoglobulin constant domains, the effect of β2-microglobulin (β2µ) on the expression of Fc receptors on human peripheral blood lymphocytes was studied. Treatment of peripheral blood lymphocytes (PBL) at 4°C with β2-microglobulin resulted in an increase in the percentage of lymphocytes expressing receptors for the Fc portion of IgG (Fcγ) from 34% in untreated preparations to 54% in preparations incubated with 50 µg of β2µ/2 × 106 cells. As shown by the binding of 125I-labeled β2µ, the molecule was taken up by peripheral lymphocytes and was associated with those lymphocytes that expressed Fcγ receptors. β2µ treatment had no demonstrable effect on the expression of other lymphocyte markers—E, EAC, sIg. The increase in Fcγ receptor expression was observed on T cells. Removal of adherent cells had no effect on β2µ induced Fcγ receptor expression, but the increased Fcγ receptor expression was abrogated by treatment with rabbit anti-human β2µ F(ab′)2 fragments. These findings suggest that high concentrations of β2µ exert effects on lymphocyte surfaces that may have functional as well as structural consequences in regulation of the immune system.