We have demonstrated that degranulation from normal human neutrophils in whole blood was stimulated by low concentrations of lithium salts and was produced by noncytolytic means. Significant amounts of beta-glucuronidase could be released from the primary granules, in addition to vitamin B12- binding protein from the secondary granules, by 10 mM lithium. Release was almost totally inhibited by 1 mM fluoride, under the same conditions. There was no release of lactate dehydrogenase and no loss of viability of cells incubated in either lithium or fluoride at the concentrations used. Lithium was also observed to have no effect on reactive oxygen production by phagocytic stimulation of isolated neutrophils. In addition, lithium and fluoride were shown to manipulate the intracellular levels of cAMP. The results demonstrated a direct effect of lithium on release of inflammatory mediators from neutrophils in vitro. The methods used also provide a simple and effective test to study an important function of neutrophil activity and can be used to evaluate degranulation in a number of clinical conditions.