An optimal immune response should differentiate between harmful and innocuous antigens. Primitive systems of innate immunity, such as the complement system, may play a role in this distinction. When activated, the C3 component of complement attaches to potential antigens on microorganisms. To determine whether this alters acquired immune recognition, mice were immunized with a recombinant model antigen, hen egg lysozyme (HEL), fused to murine C3d. HEL bearing two and three copies of C3d was 1000- and 10,000-fold more immunogenic, respectively, than HEL alone. Thus, C3d is a molecular adjuvant of innate immunity that profoundly influences an acquired immune response.