Macrophages have been shown to produce C3 and to bear Fc receptors (FcR), and besides the various C3 receptors, they possess C3b acceptors (C3bA) as well as surface proteases capable of cleaving C3. Using the immune adherence method, we demonstrated that the amount of covalently fixed (i.e., C3bA-bound) C3b is markedly increased upon cell stimulation by phorbol myristate acetate or aggregated IgG, even in the absence of C3. The enhancement of nascent C3b (C3bx) binding to C3bA on these cells could be reversed by inhibiting the process at different stages, using either cycloheximide, phenyl-methyl-sulphonyl-fluoride, salycil hydroxamic acid, or methylamine. On the basis of our present results and earlier results, we propose a self-regulatory mechanism by which activated, C3-producing macrophages cleave C3 by their surface proteases. C3bx generated in this way fixes covalently to C3bA of the producer cells, resulting in the inhibition of FcR on these cells.