Zinc is essential for immunologic function; therefore, it has been postulated that elevated serum levels of zinc might lead to improved immune responses. However, it is not known whether or how serum zinc levels contribute to a clinically relevant mechanism of immunologic activation. In our studies with human peripheral blood mononuclear cells and whole blood, the zinc level selectively enhanced the biologic activity of endotoxin. The combination of nonstimulatory doses of lipopolysaccharide (LPS) and nonstimulatory concentrations of zinc led to the secretion of large amounts of interleukin (IL)-1 beta. In contrast, zinc levels specifically down-regulated monocyte activation caused by some superantigens, staphylococcal enterotoxin A and E and Mycoplasma arthritidis--derived superantigen, but not toxic shock syndrome toxin-1. This demonstrates that zinc levels control IL-1 beta secretion after both LPS and superantigen challenge within a clinically relevant range of concentrations. Our data suggest that the indications and contraindications for clinical zinc supplementation should be reconsidered.