Homologous restriction factor (HRF) is a complementary regulatory protein found on the surface of human erythrocytes and other cell types. It has the function of blocking the lytic action of the membrane attack complex (MAC) of complement when incorporated into a membrane. HRF was found to inhibit not only the MAC composed of the proteins C5b-9, but also the C5b-8 complex. When 125I-labelled HRF was allowed to insert into an erythrocyte target, lysis by C5b-8 was reduced by about 80%. When human erythrocytes were treated with antibody to HRF, which bound to and presumably blocked the action of HRF, lysis by C5b-8 increased. This increase was not caused by additional binding of C8 on the cell membrane. When HRF was inserted into a target cell membrane, it had the effect of reducing the amount of C9 that could bind to very low levels, in one experiment from 6000 molecules per cell to about 500 molecules per cell. When this value was compared to the number of C7 molecules that bound, it was found that HRF reduced the amount of C9 bound to the level of C7 that was bound. HRF seemed to reduce the number of molecules of C9 that could bind to the C5b-8 complex so that only one C9 bound per complex.