AbstractCD47 functions as a marker of self on red blood cells (RBCs) by binding to signal regulatory protein alpha on macrophages, preventing phagocytosis of autologous RBCs by splenic red pulp macrophages, and Fcγ receptor (FcγR)– or complement receptor–mediated phagocytosis by macrophages in general. RBC senescence involves a series of biochemical changes to plasma membrane proteins or lipids, which may regulate phagocytosis by macrophages. Here, we investigated whether CD47 on experimentally senescent murine RBCs affects their phagocytosis by macrophages in vitro. Clustering of CD47 with antibodies was more pronounced in the plasma membrane of untreated RBCs, compared with that in in vitro oxidized RBCs (Ox-RBCs). Phagocytosis of Ox-RBCs was mediated by scavenger receptors (SRs) distinct from SR-A or CD36 and required serum factors. We found that wild-type (WT) and CD47−/− Ox-RBCs were phagocytosed equally well by macrophages in the presence of serum, suggesting that phagocytosis via SRs is not inhibited by CD47. Despite this, FcγR-mediated phagocytosis of IgG-opsonized Ox-RBCs was strongly inhibited by CD47. These data suggest that based on the specific prophagocytic receptors mediating uptake of senescent RBCs, the phagocytosis-inhibitory role of CD47 may be more or less involved.