Serum amyloid A (SAA) is an acute phase reactant whose levels in the blood rise as part of the body's response to stress and inflammation. Previous studies have suggested that SAA may carry an anti-inflammatory potential. We evaluated the effects of SAA on human neutrophils activated by N-formyl-methionyl-leucyl-phenylalanine (fMLP) in vitro. At concentrations higher than 10 µg/mL, SAA inhibited neutrophil myeloperoxidase (MPO) release. This effect was located in the N-terminal-that is, amino acid residues 1-14-of the SAA molecule. Directed neutrophil migration was inhibited at the same SAA concentrations. Several amino acid residues (1-14, 15-104, 83-104) contributed to this effect. Neutrophil 02-production was inhibited at low concentrations of SAA (0.1 to 1 µg/ml) and was stimulated at concentrations higher than 50 µg/mL. Neutrophil O2-production induced by phorbol myristate acetate (PMA) and O2-generated by the xanthine-xanthine oxidase reaction were not affected by SAA. These results add to previous data suggesting that SAA, at concentrations recorded in the serum during inflammation, modulates neutrophil function; thus it may play a role in the down-regulation of the inflammatory process.