Neutrophil functions, which play an important role in the antibacterial host defense system, are inhibited by various anesthetics and surgical procedures. Histamine H2-receptor antagonists are perioperatively used as a prophylaxis against acid aspiration syndrome or stress ulceration. We examined the effect of cimetidine, ranitidine, and famotidine, at clinically relevant concentrations and at 10 and 100 times this concentration, on several aspects of human neutrophil function using an in vitro system. The three H2-receptor antagonists did not impair neutrophils' chemotaxis or phagocytosis. Cimetidine and famotidine inhibited superoxide (O2-) and hydrogen peroxide (H2O2) production of the neutrophils in a dose-dependent manner, although the inhibitory effects were minimal. In contrast, ranitidine failed to change O2- or H2O2 production of neutrophils. The three H2-receptor antagonists did not scavenge these reactive oxygen species generated by the xanthine-xanthine oxidase system. The increase in intracellular calcium concentrations in neutrophils by a stimulant were dose-dependently attenuated with cimetidine or famotidine. This decreasing effect of the drugs on [Ca2+]i in neutrophils may represent one of mechanisms responsible for inhibition of reactive oxygen species generation. IMPLICATIONS: Neutrophils play a pivotal role in the antibacterial host defense system and tissue injury. We found that cimetidine and famotidine slightly reduced the O2- or H2O2 production of neutrophils in a dose-dependent manner, although ranitidine failed to do so. At least ranitidine does not seem to have any deleterious effect on neutrophil function, which is clearly an important consideration in its use in severely ill patients.