The effect of sodium fluoride (NaF) on superoxide generation and cyclic adenosine monophosphate (cAMP) levels in human neutrophils and monocytes was investigated. NaF (> 10 mM) stimulated superoxide (O2-) production in both cell types in a time dependent manner. NaF (0.5 to 20 mM) increased cAMP levels by 1.5- to 3-fold in both neutrophils and monocytes. Increases in cAMP levels were time-dependent; the maximal level was attained within 5 minutes after the addition of NaF, and cAMP levels remained elevated for up to 10 minutes. Only high concentrations of NaF (10 and 20 mM) increased both cAMP levels and O2- production. Therefore, a direct role of cAMP in O2- generation is not likely. It is speculated that since NaF (> 10 mM) can complex with extracellular Ca++, and thus reduce free Ca++ concentration required for O2- generation, a NaF-dependent increase in cAMP may restore cytosolic free Ca++ by mobilizing intracellular stores of Ca++. Further, in view of the proposed involvement of a phosphorylation-dephosphorylation mechanism in the regulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, we speculate that NaF, by inhibiting phosphoprotein phosphatase activity, may indirectly activate the NADPH oxidase system and thus superoxide generation.