Human alpha 1-acid glycoprotein (AGP) has been shown to modulate various cellular and humoral immune reactions in vitro. Using glycosidase-modified derivatives of AGP, the importance of its carbohydrate moiety with regard to these effects has been noted. In normal serum, three molecular AGP forms interacting differently with concanavalin A (Con A) are present. The ratio of these forms is often changed during various physiopathological conditions. In this study, we could show that differences exist between the three AGP forms with regard to their immunomodulatory effectiveness. At physiological concentrations, the Con A-nonreactive variant AGP-A induced a stronger inhibition of the anti-CD3 stimulated lymphocyte proliferation than the other forms. Interestingly, AGP-A was also found to be responsible for the stimulation of lymphocyte proliferation induced by low AGP concentrations in vitro. Both immunomodulatory effects of AGP were abrogated by desialylation of the glycoprotein. These results support an immunomodulatory role of AGP in conditions characterized by a changed ratio of the differently glycosylated AGP forms.