Fluoride activation of neutrophils was found to be associated with phosphoinositide turnover, as monitored by the time-dependent accumulation of inositol phosphates. Unlike phosphoinositide turnover induced by the chemotactic peptide, formylmethionylleucylphenylalanine, that induced by fluoride was not inhibited by pretreatment with pertussis toxin. The translocation of protein kinase C activity from the cytosolic to the membrane compartment was also observed in fluoride-stimulated cells. We have proposed that the mode of action of this halide ion involves interaction with a GTP-binding protein which serves as an intermediary unit between the receptors for inflammatory stimuli and the phosphoinositide-specific phosphodiesterase.