Until now, there have been no measurements of the in vivo stability of red-blood-cell-bound C3d and C4d subfragments of the third and fourth components of human complement. We have recently described a radiolabeled antiantiglobulin method for measuring RBC-bound C3d and have demonstrated that small amounts of C3d are present on RBC of all normal subjects tested. In the present study, the method was applied to follow the increments above baseline of RBC-bound C3d and C4d produced by autotransfusing 3 normal volunteers with 160–200 ml of RBC strongly coated in vitro by C3d and C4d. Posttransfusion measurements were carried out over 21–34 days. Immediate and long-term in vivo survival of the transfused RBC was unimpaired by C3d and C4d coating. Of the bound C3d antigen, 85%–95% disappeared from circulating RBC in 5–8 days; the remainder disappeared more slowly, with half-times in the range of 8–29 days. C4d antigen disappeared substantially more slowly, describable by a single exponential function in 2 of the 3 subjects, with half-times in the range of 12–31 days. Recognition of the in vivo instability of RBC-bound C3d helps in interpreting steady-state and changing levels of RBC C3d coating in a variety of alloimmune and autoimmune disorders.