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The functional capacity of lactoferrin (LF) to act as a negative feedback regulator of myelopoiesis has been investigated and shown to depend on the structure of the molecule itself and on the presence and absence of agents that can modulate its activity. LF has a specific requirement for iron (Fe) in terms of its functional capacity and is most effective in inhibiting the production of granulocyte-macrophage colony stimulating activity (GM-CSA) from monocytes and macrophages when it is fully saturated with Fe. LF saturated with copper (Cu) or zinc (Zn) is functionally ineffective; moreover, Cu and Zn actually interfere with the inhibitory properties of Fe-saturated LF. A radioimmunoassay for LF did not distinguish between these functionally active and inactive samples of metal-unsaturated and metal-saturated LF. Bacterial lipopolysaccharide (LPS), lithium, testosterone, and estradiol abrogate LF inhibition of GM-CSA production, but the mechanism of LPS and lithium abrogation may be different since lithium, but not LPS, could equally reverse LF inhibition of C3H/HeJ (poor LPS responder) and C3HeB/FeJ (normal LPS responder) macrophages. While the corticosteroids, hydrocortisone and dexamethasone, do not influence GM-CSA production or LF activity, they do block the LPS abrogation of LF action. The specificity of LF for inhibition of monocyte-macrophage GM-CSA production was further substantiated as LF has no effect on B-lymphocyte CSA production by mouse macrophages, “pre-CFU-GM” stimulatory activity production by adherent mononuclear bone marrow cells, the release of lysozyme from human monocytes and mouse macrophages, the release of β-glucuronidase from J774 cells, and the production of plasminogen activator by mouse macrophages. The specificity of LF for the mononuclear phagocytic series was also defined, as LF did not bind to or inhibit GM-CSA production by human lymphocytes. These results indicate the complex interactions that may modify the in vivo action of LF.