Normal circulating red blood cells (RBCs) and platelets have been shown to have small amounts of IgG on their membranes. The cell-bound IgG may be cytophilic (IgG nonspecifically adsorbed from the plasma) and/or IgG autoantibody. It has been suggested that most of the RBC-bound IgG is on older RBCs and is an autoantibody directed against senescent cell antigen (SCA). The accumulation of this RBC-bound IgG leads to Fc-dependent removal of senescent RBCs by macrophages in the reticuloendothelial system. RBCs also have complement components on their membrane; it is not clear how this accumulates on RBCs and whether it has a physiologic function. This small amount of nonpathogenic RBC-bound IgG is not detected by the antiglobulin test. It is still unclear whether the major difference between pathogenic and nonpathogenic IgG autoantibodies is qualitative, quantitative, or both. Seemingly healthy blood donors (1 in 1,000 donors) and patients without hemolytic anemia (up to 8% of patients) have increased amounts ( > 200 molecules/RBC) of RBC-bound IgG and complement that is detected by the antiglobulin test. This RBC-bound IgG has been shown to be an IgG autoantibody directed against blood group antigens, and/or IgG anti-idiotype, and/or IgG nonspecifically adsorbed onto the RBC membrane when plasma IgG levels are high. Most patients with autoimmune hemolytic anemia (AIHA) have RBC-bound IgG and/or complement detectable by the antiglobulin test. Most of the RBC-bound IgG is of the IgG1 subclass, whether one examines the RBCs of healthy blood donors or hospitalized patients with and without AIHA. Although the quantity of RBC-bound IgG is generally higher in patients with AIHA, there is no clear correlation with the quantity of RBC-bound IgG and the rate of in vivo RBC destruction. There is some recent evidence that the SCA autoantibody may at times be pathogenic and cause autoimmune disease.