The sera of four patients with chronic hemolytic anemia due to cold agglutinins deposited C' globulins on normal red cells at 37 degrees C. The circulating cells of the patients were heavily coated with C' complex and were relatively resistant to C' hemolysis by cold agglutinin. Such red cells were removed from the patients' circulation at an exponential rate with (51)Cr t((1/2)) that varied from 7 to 19 days. Normal red cells were removed rapidly by hepatic sequestration during the first hours in the patients' circulation. Thereafter, a slower rate of abnormal destruction occurred which was associated with the accumulation of C' complexes on the red cell and the development of resistance to C' hemolysis by cold agglutinin. Normal red cells coated with sufficient C' complex by action of cold agglutinins in vitro to produce resistance to C' hemolysis by cold agglutinins demonstrated varying degrees of improved survival during the first hours in the circulation of three of the patients. The levels of serum C' were reduced in all four patients with chronic hemolytic anemia due to cold agglutinins. Transfusion of large volumes of normal red cells into two patients further reduced serum C'. (51)Cr-labeled normal red cells survived longer after red cell transfusions than before, because of less rapid destruction during the first hours in the circulation. The reduction in serum C' levels appeared responsible for the improved survival. In subjects without cold agglutinins, the presence of the spleen decreased the survival of red cells from a patient who had previously undergone splenectomy. Splenic removal also predominated in the reduced survival of autologous red cells in one patient. Neither hepatic nor splenic mechanisms predominated in removing autologous C'-coated cells in the other two patients.