Superantigens are products of bacteria with dual affinity for HLA-DR and the variable region of the beta chain of the T cell receptor, leading to the stimulation of large numbers of T cells. Because there is evidence for the involvement of superantigens in various disease conditions in which intravenous IgG (IVIgG) is used as therapy, the purpose of the present study was to determine if IVIgG contains antibodies inhibitory to T cell stimulation by the superantigens. ELISA and Western assays revealed high concentrations of antibodies in the pooled IgG against eight different staphylococcal toxin (Staph-toxin) superantigens. The IVIgG inhibited in vitro stimulation of human peripheral blood T cells by the Staph-toxins, but did not inhibit responses elicited by phytohemagglutinin or anti-CD3. Inhibition was mediated by Staph-toxin-specific antibodies as shown by affinity adsorption depletion studies. The antibodies functioned by inhibiting the binding and/or presentation of Staph-toxins by DR+ accessory cells. In conclusion, this report is the first to show that normal pooled IgG contains antibodies against a major group of the superantigens, the Staph-toxins, and that the antibodies can inhibit Staph-toxin-elicited T cell activation, suggesting a possible immunoregulatory role for the antibodies in vivo.