Several recent reports have described a high incidence of anaphylactic reactions in patients being dialyzed with high-flux membranes while simultaneously using angiotensin-converting enzyme inhibitors. Many of these reports implicate polyacrylonitrile (PAN) as the membrane commonly involved in these reactions. To elucidate potential mechanisms of these anaphylactic reactions, whether dialysis membranes can activate the Hageman factor-dependent (contact) pathways as assessed by the in vitro generation of activated Hageman factor (Hfa), as well as the formation of kallikrein and subsequent bradykinin generation was examined. Both cuprophane (CUP) and PAN membranes were able to activate Hageman factor and convert prekallikrein to kallikrein as measured by an ELISA against kallikrein-C1-inactivator complexes. Subsequently, the active kallikrein was able to cleave bradykinin from its endogenous substrate, high-molecular-weight kininogen. However, it was found that the PAN membrane consistently led to an earlier and significantly higher formation of Hfa and kallikrein when compared with CUP. Importantly, there was also a pronounced but transient generation of bradykinin by the PAN membrane, in contrast to slower bradykinin formation by CUP, with both normal and uremic blood. It was proposed that the early and vigorous bradykinin generation induced by the contact of blood with PAN could explain, in part, the pathogenesis of the reported anaphylactoid reactions.