CVF administered before immunization can profoundly depress humoral responses in C-sufficient mice. In AKR/J C5- mice given CVF before i.v. immunization with SRBC, only IgG levels were depressed, IgM titers being equivalent to those of untreated controls. The immunosuppressive effect became inapparent when the i.p. route of immunization was adopted. In DBA/2J C5- mice reduction of both IgG and IgM titers was observed irrespective of the route of immunization. The degree of suppression was, however, much more marked when mice were challenged intravenously. Essentially identical results were obtained with C5+ DBA/1J mice. These studies indicate that immunosuppression by CVF is unrelated to activation of the late C components. The significance of these findings is discussed with reference to the possibility that the generation of biologically active C fragments in conjunction with a C3 deficiency may account for immunosuppression by CVF.