Serum amyloid P component (SAP) and C-reactive protein (CRP) are opsonins that react with nuclear autoantigens targeted in systemic autoimmunity. CRP and SAP bind to apoptotic and necrotic cells, which are potential sources of these autoantigens. We have recently determined that the receptors for CRP on phagocytic cells are Fcγ receptors. The goal of this study was to determine whether CRP and SAP promote phagocytosis of apoptotic cells and to identify the receptors involved. Apoptosis was induced in human neutrophils (PMN) and the Jurkat T-cell line by UV-irradiation. SAP treatment of apoptotic human PMN increased ingestion by autologous macrophages. Both SAP and CRP increased ingestion of apoptotic, but not normal Jurkat cells by J-774 macrophages and mouse peritoneal macrophages. Neither SAP nor CRP increased ingestion of apoptotic Jurkat cells by macrophages from FcR γ-chain deficient mice, which lack FcγRI and FcγRIII. Inhibition of FcγRIII-mediated uptake using mAb 2.4G2 eliminated opsonization by SAP, but not by CRP. These results indicate that pentraxins promote uptake of apoptotic cells through FcγRI and/or FcγRIII. Ingestion through these receptors is expected to alter the pattern of cytokine production and antigen presentation in response to apoptotic cells.