Recently, we described the presence of a blocking factor (BF) in rat serum, which inhibited the histamine release from rat mast cells in vivo and in vitro. The blocking activity was demonstrated in human serum as well. Qualitative analysis of the purified preparations demonstrated a major component with an apparent molecular weight of 70,000 daltons. In human serum the blocking factor was identified as transferrin (TF) by serological and biochemical methods. BF (DEAE-peak 1) and the iron binding proteins transferrin and lactoferrin (LF) are shown to inhibit the histamine release in vitro. The dose response curves reveal that inhibition by these proteins is dependent on their degree of iron saturation. Furthermore, unlike lactoferrin, the effects of transferrin and BF (DEAE-peak 1) follow the same pattern. Their mechanism of action remains to be elucidated.