Bovine milk IgG markedly inhibits the pokeweed mitogen (PWM)-induced secretion of immunoglobulins from human peripheral blood mononuclear cells. Heat-aggregated bovine milk IgG is even more inhibitory, demonstrating significant inhibition when levels as low as 5-9 micrograms/ml are continuously present in the in vitro 14-day culture system. However, bovine serum IgG, regardless of its state of aggregation, and control proteins have little effect on PWM-induced secretion of human IgG, IgA, and IgM. In a similar fashion, goat milk IgG, especially when aggregated, inhibits human antibody secretion whereas goat serum IgG does not. Inhibition appears to be mediated by Fc gamma receptors since F(ab')2 fragments of milk-derived bovine IgG do not inhibit PWM-induced antibody secretion. The continuous presence of bovine milk IgG is not essential since preincubation of milk IgG with PWM and human mononuclear cells for 24 hr also results in inhibition of human immunoglobulin secretion. In examining potential mechanisms of inhibition, it was found that bovine milk IgG, bovine serum IgG, and another chitin-containing protein, bovine thyroglobulin, each caused a small and equal inhibition of the binding of 125I-labeled PWM to human mononuclear cells, yet only the milk IgG inhibited antibody production. These studies raise the question of whether bovine milk IgG might modulate the human immune system in vivo.