Previous work in our laboratory showed that Zn2+ enhanced the rate of kallikrein generation by dextran sulfate (DxSO4) in dialyzed normal plasma, but not in Fitzgerald or Hageman prismas. This could be partially explained by a marked effect of Zn2+ on factor XII autoactivation, and our present work involves zinc effects on other reactions of contact activation. At physiological ionic strength (0.15 μ), the kcat/Km for Xlla activation of prekallikrein (PK) was 0.62 μM™1 s™1 which was increased to 4.35 μM™1 s™1 by the presence of 25μg/ml DxSO4. High molecular weight kininogen (HMK) at 40 nM further increased this to 10.8 μM™1 s™1 , and 5 ¼M Zn2+ had no effect. To determine whether these cofactors promote a surface-dependent activation of PK by XIIa under conditions which weaken the protein-surface interactions, the kinetics were examined at 0.3μ. At this ionic strength, kcat/Km was 0.18 μM™1 s™1 and was unchanged by 25μg/ml DxSO4. This was increased to .805 μM™1 s™1 by 150 nM HMK and further increased 10-fold to 8.35 μM™1 s™1 by 10 μM™1 Zn2+ . Qualitative results were obtained at 0.3 μ for the other reciprocal reaction, XII activation by kallikrein (K). To observe XII activation within 2 hours, both 10 μM Zn2+ and 25 μM HMK were essential, indicating that these cofactors have a very large enhancing effect on the kinetics of this reaction. Chromatography of HMWK on DxSO4-agarose ^ljiowed elution of the protein at 0.42 M NaCl in the absence of Zn2+ ,but at 0.88M in its presence, providing evidence that Zn+ markedly increases the affinity of HMK for DxSO4. Our results are consistent with the increased activation rates observed in the presence of Zn2+ and HMK due to enhanced binding affinity of the reacting proteins to surfaces. This is likely to be essential for proper function of the contact system in blood, where many other proteins compete for surface. Supported by USPHS grant HL-25670