Sera from patients with acute lymphoblastic leukemia or active transplant rejection contain high concentrations of a material which regulates C3 and C3b activity. Preliminary isolation of this material reveals that it is able to interfere with both C3 and C3b activity. Lysis of EAC4̄2 by purified C3–C9 or C3 consumption by is inhibited if this material is present when C3 is added. There is no effect if this material is removed before the addition of C3 implying an interaction with native C3 or a C3-like structure which competes with the active enzymatic sites. If, however, this material is added to or cells and then removed, addition of C3bINA or C3bINA and β1H has no effect on the subsequent lysis by C5–C9 () or factors B, D, and C3–C9 (EAC43b). These latter results imply a direct irreversible effect of this substance on bound C3b.