Fluoride ion, at concentrations above 10 mM, was found to elicit a rise in intracellular calcium levels in neutrophils, as monitored by changes in Quin 2 fluorescence intensity. The calcium mobilization response was characterized by a lag period of 4 to 10 min. and a prolonged duration of action (greater than 20 min.). In contrast, the chemotactic peptide, formylmethionyl-leucyl-phenylalanine, induced a rise in intracellular calcium concentrations which peaked within 1 min. Preincubation of the cells with 1 microgram/ml pertussis toxin resulted in inhibition of the formylmethionyl-leucyl-phenylalanine induced response, but not that mediated by fluoride. Recent evidence suggests that the formylmethionyl-leucyl-phenylalanine receptor is coupled to phospholipase C and phosphoinositide degradation through a guanine nucleotide binding protein susceptible to inhibition by pertussis toxin. Present results suggest that fluoride ion may serve to activate this protein in a manner resistant to inhibition by pertussis toxin.