Cells that become necrotic or apoptotic through tissue damage or during normal cellular turnover are usually rapidly cleared from the circulation and tissues by phagocytic cells. A number of soluble proteins have been identified that facilitate the phagocytosis of apoptotic cells, but few proteins have been defined that selectively opsonize necrotic cells. Previous studies have shown that histidinerich glycoprotein (HRG), an abundant (ϳ100 g/ml) 75-kDa plasma glycoprotein, binds to cell surface heparan sulfate on viable cells and cross-links other ligands, such as plasminogen, to the cell surface. In this study we have demonstrated that HRG also binds very strongly, in a heparan sulfate-independent manner, to cytoplasmic ligand(s) exposed in necrotic cells. This interaction is mediated by the amino-terminal domain of HRG and results in enhanced phagocytosis of the necrotic cells by a monocytic cell line. In contrast, it was found that HRG binds poorly to and does not opsonize early stage apoptotic cells. Thus, HRG has the unique property of selectively recognizing necrotic cells and may play an important physiological role in vivo by facilitating the uptake and clearance of necrotic, but not apoptotic, cells by phagocytes.Cell death is vital for the morphological shaping of tissues during development and for the sculpting of functionally appropriate cellular repertoires as well as for protecting an individual from viral infections and pathogenic microorganisms (1, 2). Selective cell death continues to play a role in the homeostasis of mature tissues, such as the deletion of immune cells in the attenuation of an immune response (3) and the elimination of cells that have become functionally inappropriate, including virally infected and transformed cells (4). Apoptosis and necrosis represent two different forms of cell death and are characterized by distinct morphologies. Rapid and efficient phagocytic removal of dying cells is a key feature of apoptosis, whereas the role and extent of phagocytosis in the clearance of necrotic cells is not well documented. It is thought, however, that by engulfing necrotic and apoptotic cells phagocytes of the innate immune system not only provide a first line of defense against microbial pathogens but also dispose of self-antigens that are released from dying cells (5).Apoptosis is characterized by an orderly sequence of internal events, including chromatin condensation that precedes the loss of cellular integrity (6). Apoptotic cells also display phosphatidylserine and altered membrane carbohydrates on their surface. Multiple ligands and receptors have been implicated in the recognition and uptake of apoptotic cells by phagocytes prior to membrane lysis, thus preventing release of potentially toxic and immunogenic intracellular substances into tissues. In addition, the binding and/or uptake of apoptotic cells inhibits proinflammatory cytokine production (7). When there are disturbances in either apoptosis or the phagocytosis of apoptotic cells, antibodies against subsequently exp...