Inhibitors of mast cell tryptase and chymase can be effective as mast cell stabilising compounds. Lactoferrin has been reported to inhibit tryptase activity, but its actions on other serine proteases of mast cells and its potential to alter mast cell function are not known. We have examined the ability of lactoferrin to inhibit mast cell tryptase, chymase and cathepsin G, and investigated its potential to modulate the activation of human mast cells. Enzymatically dispersed cells from human skin, lung and tonsil were challenged with anti-IgE or calcium ionophore A23187, following incubation with recombinant human lactoferrin, and histamine release determined. IgE-dependent histamine release from skin mast cells was inhibited by up to 50% following incubation with lactoferrin (50 or 500 nM). Tonsil mast cells were also stabilised by lactoferrin, but not those from lung. Calcium ionophore A23187-induced histamine release was not altered by lactoferrin. A double-labelling immunocytochemical procedure revealed the presence of lactoferrin in 4-6% of mast cells, and this proportion increased to 40% following incubation with lactoferrin. Lactoferrin did not inhibit cleavage of synthetic substrates by tryptase and chymase directly, though it was able to diminish the ability of heparin to stabilise tryptase. Cathepsin G activity was inhibited by lactoferrin. The ability of lactoferrin to inhibit IgE-dependent activation of human mast cells and modulate protease activity suggests that the release of this neutrophil product may have a role in the downregulation of allergic inflammation.