We earlier reported the IgE-mediated release of a basophil kallikrein of anaphylaxis (BK-A) which, like plasma kallikrein, is an arginine esterase and cleaves human plasma kininogen generating immunoreactive kinin. We herein report that, like plasma kallikrein, preparations rich in this basophil protease also activate human Hageman Factor by proteolytic cleavage of the zymogen molecule into light and heavy chains. These fragments of 28,000 and 52,000 daltons are similar in size to those produced during activation of Hageman Factor by plasma kallikrein. Exposure of Hageman Factor (bound to a negatively charged surface) to BK-A led to the proteolytic cleavage of Hageman Factor producing a 28,000 molecular weight fragment (HFa) which is functionally active and capable of activating prekallikrein to kallikrein. We conclude that, during anaphylaxis, basophils may release a protease that is capable of cleaving and activating Hageman Factor, thus providing a mechanism for initiating the in vivo activation of the Hageman Factor dependent systems.