Neutralization of the negative charges of heparin by polycations in the fluid phase suppressed the inhibitory effect of heparin on the generation of the C3b-dependent amplification convertase of complement C3b,Bb. Polymeric polycations alone, whether natural or synthetic, prevented formation of the cell-bound amplification convertase and of the fluid-phase interaction of C3b, B and D, in a dose-related fashion in the concentration range of 1 to 2 X 10(-8)M for poly-L-lysine (PLL) 50,000. The inhibitory effect of PLL on formation of the cell-bound convertase was independent of the presence of P. Percent inhibition of C3b,Bb,P and C3b,B,P formation was constant when the convertases were formed with a fixed concentration of PLL and increasing amounts of B; PLL was more effective in preventing convertase formation on cells bearing low numbers of C3b and developed with high doses of B. The decay of the preformed P stabilized convertase was not altered by PLL whether in the presence or absence of H. Thus, polycations in the fluid phase specifically inhibit formation of the amplification C3 convertase by preventing the association between C3b and B, most likely by acting on C3b. The low-affinity interaction between C3b and B is a privileged site for natural or pharmacological modulation of complement by polyelectrolytes.