Anti‐C3d sera were raised to different C3d antigens or to the same C3d antigen by different methods. Although identical by immunoprecipitation studies, the various anti‐C3d sera showed differences in specificities against bound C3d antigen. Such differences were observed wih red blood cells coated with C3d invivoand invitro. Antisera made to the C3d− KAF antigen detected fewer molecules/cell on C3d−tryp cells than did antisera made to the C3d−tryp antigen. The converse was true for C3d− KAF cells. “Saturation” experiments indicated that different anti−C3d detected different “subpopulations” of bound C3d. C3d bound to red blood cellsin vivowas, in at least one case, detectable by some anti‐ C3d sera but not by others. Such differences in anti‐C3d specificity may be important in determining the optimal characteristics of anti‐C3d antiglobulin serum