The superoxide (O2) production by phagocytes (neutrophils plus monocytes) and the lactoferrin release by neutrophils were measured in normal volunteers before and after the oral administration of the anti-inflammatory drug nimesulide. The chemotactic factor N-formylmethionyl-leucyl-phenylalanine (FMLP) and opsonized zymosan particles (OPZ) were used as activating stimuli. The oral administration of nimesulide lowered the phagocyte ability to generate O2- in response to both FMLP (percent inhibition = 67.62) and OPZ (percent inhibition = 36.75). The lactoferrin release by neutrophils was unaffected, proving that the drug does not affect the exocytosis of specific granules. The results provide direct evidence that the oral administration of nimesulide efficiently reduces the oxidative potential of phagocytes, particularly neutrophils, without interfering with mechanisms related to exocytosis of specific granules and involved in the amplification of the cell responses to inflammatory mediators.