Histamine release caused by calcium ionophore A23187 and anti-IgE was examined in leukocyte suspensions from 8 healthy individuals. Staphylococcus aureus, lipopolysaccharide (LPS) from Salmonella typhimurium and influenza A virus were found to enhance the histamine release but did not release histamine per se. The potentiation of mediator release depends on a non-transient signal since the potentiating effect was also obtained by preincubation of the cells with LPS followed by wash-out and stimulation of the cells with anti-IgE. The potentiation was abolished or reduced by galactose, N-acetyl-glucosamine, α-methyl-d-glucoside, α-methyl-d-mannoside, N-acetylneuraminic acid and lactose, but not by glucose. These findings indicate that the enhancement of mediator release by bacteria, endotoxin, and virus depends on a sugar-mediated reaction.